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Sample records for hepatic cytochrome p450-dependent

  1. Cytochrome P450-Dependent Metabolism of Caffeine in Drosophila melanogaster

    Coelho, Alexandra; Fraichard, Stephane; Le Goff, Gaëlle; Faure, Philippe; Artur, Yves; Ferveur, Jean-François; Heydel, Jean-Marie

    2015-01-01

    Caffeine (1, 3, 7-trimethylxanthine), an alkaloid produced by plants, has antioxidant and insecticide properties that can affect metabolism and cognition. In vertebrates, the metabolites derived from caffeine have been identified, and their functions have been characterized. However, the metabolites of caffeine in insects remain unknown. Thus, using radiolabelled caffeine, we have identified some of the primary caffeine metabolites produced in the body of Drosophila melanogaster males, including theobromine, paraxanthine and theophylline. In contrast to mammals, theobromine was the predominant metabolite (paraxanthine in humans; theophylline in monkeys; 1, 3, 7-trimethyluric acid in rodents). A transcriptomic screen of Drosophila flies exposed to caffeine revealed the coordinated variation of a large set of genes that encode xenobiotic-metabolizing proteins, including several cytochromes P450s (CYPs) that were highly overexpressed. Flies treated with metyrapone—an inhibitor of CYP enzymes—showed dramatically decreased caffeine metabolism, indicating that CYPs are involved in this process. Using interference RNA genetic silencing, we measured the metabolic and transcriptomic effect of three candidate CYPs. Silencing of CYP6d5 completely abolished theobromine synthesis, whereas CYP6a8 and CYP12d1 silencing induced different consequences on metabolism and gene expression. Therefore, we characterized several metabolic products and some enzymes potentially involved in the degradation of caffeine. In conclusion, this pioneer approach to caffeine metabolism in insects opens novel perspectives for the investigation of the physiological effects of caffeine metabolites. It also indicates that caffeine could be used as a biomarker to evaluate CYP phenotypes in Drosophila and other insects. PMID:25671424

  2. Cytochrome P450-dependent metabolism of caffeine in Drosophila melanogaster.

    Alexandra Coelho

    Full Text Available Caffeine (1, 3, 7-trimethylxanthine, an alkaloid produced by plants, has antioxidant and insecticide properties that can affect metabolism and cognition. In vertebrates, the metabolites derived from caffeine have been identified, and their functions have been characterized. However, the metabolites of caffeine in insects remain unknown. Thus, using radiolabelled caffeine, we have identified some of the primary caffeine metabolites produced in the body of Drosophila melanogaster males, including theobromine, paraxanthine and theophylline. In contrast to mammals, theobromine was the predominant metabolite (paraxanthine in humans; theophylline in monkeys; 1, 3, 7-trimethyluric acid in rodents. A transcriptomic screen of Drosophila flies exposed to caffeine revealed the coordinated variation of a large set of genes that encode xenobiotic-metabolizing proteins, including several cytochromes P450s (CYPs that were highly overexpressed. Flies treated with metyrapone--an inhibitor of CYP enzymes--showed dramatically decreased caffeine metabolism, indicating that CYPs are involved in this process. Using interference RNA genetic silencing, we measured the metabolic and transcriptomic effect of three candidate CYPs. Silencing of CYP6d5 completely abolished theobromine synthesis, whereas CYP6a8 and CYP12d1 silencing induced different consequences on metabolism and gene expression. Therefore, we characterized several metabolic products and some enzymes potentially involved in the degradation of caffeine. In conclusion, this pioneer approach to caffeine metabolism in insects opens novel perspectives for the investigation of the physiological effects of caffeine metabolites. It also indicates that caffeine could be used as a biomarker to evaluate CYP phenotypes in Drosophila and other insects.

  3. Rat liver microsomal cytochrome P450-dependent oxidation of 3,5-disubstituted analogues of paracetamol

    Bessems, J.G.M.; Koppele, J.M. te; Dijk, P.A. van; Stee, L.L.P. van; Commandeur, J.N.M.; Vermeulen, N.P.E.

    1996-01-01

    1. The cytochrome P450-dependent binding of paracetamol and a series of 3,5-disubstituted paracetamol analogues (R = -F, -Cl, -Br, -I, -C(H)3, -C2H5, -iC3H7) have been determined with β-naphthoflavone (βNF)-induced rat liver microsomes and produced reverse type I spectral changes. K(s,app) varied

  4. Cytochrome P-450 dependent ethanol oxidation. Kinetic isotope effects and absence of stereoselectivity

    Ekstroem, G.; Norsten, C.; Cronholm, T.; Ingelman-Sundberg, M.

    1987-01-01

    Deuterium isotope effects [/sup D/(V/K)] and stereoselectivity of ethanol oxidation in cytochrome P-450 containing systems and in the xanthine-xanthine oxidase system were compared with those of yeast alcohol dehydrogenase. The isotope effects were determined by using both a noncompetitive method, including incubation of unlabeled of [1,1- 2 H 2 ] ethanol at various concentrations, and a competitive method, where 1:1 mixtures of [1- 13 C]- and [ 2 H 6 ] ethanol or [2,2,2- 2 H 3 ]- and [1,1- 2 H 2 ] ethanol were incubated and the acetaldehyde formed was analyzed by gas chromatography/mass spectrometry. The /sup D/(V/K) isotope effects of the cytochrome P-450 dependent ethanol oxidation were about 4 with liver microsomes from imidazole-, phenobarbital- or acetone-treated rabbits or with microsomes from acetone- or ethanol-treated rats. Similar isotope effects were reached with reconstituted membranes containing the rabbit ethanol-inducible cytochrome P-450 (LMeb), whereas control rat microsomes and membranes containing rabbit phenobarbital-inducible P-450 LM 2 oxidized the alcohol with /sup D/(V/K) of about 2.8 and 1.8, respectively. Addition of Fe/sup III/EDTA either to microsomes from phenobarbital-treated rabbits or to membranes containing P-450 LMeb significantly lowered the isotope effect. Incubations of all cytochrome P-450 containing systems of the xanthine-xanthine oxidase systems with (1R)- and (1S)-[1- 2 H] ethanol, revealed, taking the isotope effects into account, that 44-66% of the ethanol oxidized had lost the 1-pro-R hydrogen. The data indicate that cytochrome P-450 dependent ethanol oxidation is not stereospecific and that cleavage of the C 1 -H bond appears to be a rate-determining step in the catalysis by the ethanol-inducible form of P-450. The contribution of hydroxyl radicals in ethanol oxidation by the various enzymic systems is discussed

  5. Certain tryptophan photoproducts are inhibitors of cytochrome P450-dependent mutagenicity

    Rannug, U.; Agurell, E.; Cederberg, H.; Rannug, A.

    1992-01-01

    Two photoproducts, derived from UV-irradiation of the amino acid L-tryptophan and with high Ah (TCDD) receptor binding affinity, were tested for genotoxic and antimutagenic effects. The two indolo[3,2-b]carbazole derivatives, with the molecular weights of 284 and 312, respectively, were tested in Saccharomyces cerevisiae strain D7 for mitotic gene conversion and reverse mutation and in strain RS112 for sister chromatid conversion and gene conversion. No significant (P > 0.05) genotoxic effects were found in strain D7, while strain RS112 showed a small but significant increase in the frequency of sister chromatid conversions. In Chinese hamster ovary (CHO) cells the two compounds induced a statistically significant but less than twofold increase in the frequency of sister chromatid exchanges (SCE). No mutations were detected when the compounds were tested in Salmonella tphimurium strains TA98 and TA100. However, both 284 and 312 acted as antimutagens on strain TA100+S9 in the presence of benzo(a)pyrene. The decrease in mutagenicity by the most potent compound 284 was 20 revertants/nmol. This effect could be explained by an inhibitory effect on the cytochrome P450-dependent ethoxyresorufin O-deethylase (EROD) activity as seen in rat hepatocytes. The two compounds were also tested with hamster cells expressing rat cytochrome P-4501A1. The results support the conclusion that this cytochrome P-450 isozyme is inhibited by the tryptophan photoproducts. Similar results were also seen with two other high affinity Ah receptor ligands the quinazolinocarboline alkaloids rutaecapine and dehydrorutaecarpine. 20 refs., 3 figs., 4 tabs

  6. Status of Resistance of Bemisia tabaci (Hemiptera: Aleyrodidae) to Neonicotinoids in Iran and Detoxification by Cytochrome P450-Dependent Monooxygenases.

    Basij, M; Talebi, K; Ghadamyari, M; Hosseininaveh, V; Salami, S A

    2017-02-01

    Nine Bemisia tabaci (Gennadius) populations were collected from different regions of Iran. In all nine populations, only one biotype (B biotype) was detected. Susceptibilities of these populations to imidacloprid and acetamiprid were assayed. The lethal concentration 50 values (LC 50 ) for different populations showed a significant discrepancy in the susceptibility of B. tabaci to imidacloprid (3.76 to 772.06 mg l -1 ) and acetamiprid (4.96 to 865 mg l -1 ). The resistance ratio of the populations ranged from 9.72 to 205.20 for imidacloprid and 6.38 to 174.57 for acetamiprid. The synergistic effects of piperonylbutoxide (PBO) and S,S,S-tributylphosphorotrithioate (DEF) were evaluated for the susceptible (RF) and resistant (JR) populations for the determination of the involvement of cytochrome P450-dependent monooxygenase and carboxylesterase, respectively, in their resistance mechanisms. The results showed that PBO overcame the resistance of the JR population to both imidacloprid and acetamiprid, with synergistic ratios of 72.7 and 106.9, respectively. Carboxylesterase, glutathione S-transferase and cytochrome P450-dependent monooxygenase were studied biochemically, for the purpose of measuring the activity of the metabolizing enzymes in order to determine which enzymes are directly involved in neonicotinoid resistance. There was an increase in the activity of cytochrome P450-dependent monooxygenase up to 17-fold in the resistant JR population (RR = 205.20). The most plausible activity of cytochrome P450-dependent monooxygenase correlated with the resistances of imidacloprid and acetamiprid, and this suggests that cytochrome P450-dependent monooxygenase is the only enzyme system responsible for neonicotinoid resistance in the nine populations of B. tabaci.

  7. CYTOCHROME P450-DEPENDENT METABOLISM OF TRICHLOROETHYLENE IN THE RAT KIDNEY

    The metabolism of trichloroethylene (Tri) by cytochrome P450 (P450) was studied in microsomes from liver and kidney homogenates and from isolated renal proximal tubular (PT) and distal tubular (DT) cells from male Fischer 344 rats. Chloral hydrate (CH) was the only metabolite con...

  8. Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway.

    Alecu, Irina; Othman, Alaa; Penno, Anke; Saied, Essa M; Arenz, Christoph; von Eckardstein, Arnold; Hornemann, Thorsten

    2017-01-01

    The 1-deoxysphingolipids (1-deoxySLs) are atypical sphingolipids (SLs) that are formed when serine palmitoyltransferase condenses palmitoyl-CoA with alanine instead of serine during SL synthesis. The 1-deoxySLs are toxic to neurons and pancreatic β-cells. Pathologically elevated 1-deoxySLs cause the inherited neuropathy, hereditary sensory autonomic neuropathy type 1 (HSAN1), and are also found in T2D. Diabetic sensory polyneuropathy (DSN) and HSAN1 are clinically very similar, suggesting that 1-deoxySLs may be implicated in both pathologies. The 1-deoxySLs are considered to be dead-end metabolites, as they lack the C1-hydroxyl group, which is essential for the canonical degradation of SLs. Here, we report a previously unknown metabolic pathway, which is capable of degrading 1-deoxySLs. Using a variety of metabolic labeling approaches and high-resolution high-accuracy MS, we identified eight 1-deoxySL downstream metabolites, which appear to be formed by cytochrome P450 (CYP)4F enzymes. Comprehensive inhibition and induction of CYP4F enzymes blocked and stimulated, respectively, the formation of the downstream metabolites. Consequently, CYP4F enzymes might be novel therapeutic targets for the treatment of HSAN1 and DSN, as well as for the prevention of T2D. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  9. Cytochrome P450-dependent N-hydroxylation of an aminoguanidine (amidinohydrazone) and microsomal retroreduction of the N-hydroxylated product.

    Clement, B; Schultze-Mosgau, M H; Richter, P H; Besch, A

    1994-07-01

    1. The first example of a P450-dependent N-hydroxylation of an aminoguanidine (amidinohydrazone) is reported for 2-amino-5-chlorobenzophenone amidinohydrazone 1 (G 256) as substrate. 2. The N-hydroxylated metabolite 2 (2-amino-5-chlorobenzophenone N-hydroxyamidinohydrazone NOH-G256) and a further metabolite of 1, the phenol 3, were identified by tlc and ms analysis. 3. The microsomal reduction of an N-hydroxyaminoguanidine (N-hydroxy-amidino-hydrazone) was also demonstrated for the transformation of 2 to 1. 4. Both the N-hydroxylation of the aminoguanidine and the retroreduction of the N-hydroxyaminoguanidine were characterized by quantitative hplc analysis. 5. The conversion of the aminoguanidine 1 to N-hydroxyaminoguanidine 2 may be considered as an analogue of the physiological N-hydroxylation of arginine to N-hydroxyarginine by NO synthases.

  10. Mechanism-based inactivation of cytochrome P-450 dependent benzo[a]pyrene hydroxylase activity by acetylenic and olefinic polycyclic arylhydrocarbons

    Gan, L.S.

    1986-01-01

    A series of aryl acetylenes and aryl olefins have been examined as substrates and inhibitors of cytochrome P-450 dependent monooxygenases in liver microsomes from 5,6-benzoflavone or phenobarbital pretreated rats. 1-Ethynylpyrene (EP), 3-ethynylperylene (EPL), cis- and trans-1-(2-bromo-vinyl)pyrene (c-BVP and t-BVP), and 1-allylpyrene (AP) serve as mechanism-based irreversible inactivators (suicide inhibitors) of benzo(a)pyrene (BP) hydroxylase, while 1-vinyl-pyrene (VP) and phenyl 1-pyrenyl acetylene (PPA) do not cause a detectable suicide inhibition of the BP hydroxylase. The mechanism-based loss of BP hydroxylase activity caused by the aryl acetylenes is not accompanied by a corresponding loss of the P-450 content of the microsomes. In the presence of NADPH, 3 H-labeled EP covalently attached to P-450 isozymes with a measured stoichiometry of one mole of EP per mole of the P-450 heme. The results of the effects of these aryl derivatives in the mammalian cell-mediated mutagenesis assay and toxicity assay show that none of the compounds examined nor any of the their metabolites produced in the incubation system are cytotoxic to V79 cells

  11. Detection of toxic effects of Cd{sup 2+} on different fish species via liver cytochrome P450-dependent monooxygenase activities and FTIR spectroscopy

    Henczova, Maria; Deer, Aranka Kiss [University of Szeged, Department of Biochemistry, P.O. Box 533, Szeged (Hungary); Komlosi, Viktoria [Chemical Research Center of the Hungarian Academy of Sciences, Department of Molecular Spectroscopy, P.O. Box 17, Budapest (Hungary); Mink, Janos [Chemical Research Center of the Hungarian Academy of Sciences, Department of Molecular Spectroscopy, P.O. Box 17, Budapest (Hungary); University of Veszprem, Faculty of Information Technology, Research Institute of Chemistry and Process Engineering; Analytical Chemistry Research Group of the Hungarian Academy of Sciences, P.O. Box 158, Veszprem (Hungary)

    2006-06-15

    The in vivo and in vitro effects of Cd{sup 2+} and the CYP1A inductor {beta}-naphthoflavone({beta}-NF) on the hepatic cytochrome P450 (Cyt 450) monooxygenases were studied in silver carp (Hypophthalmichtys molitrix V.), wels (Silurus glanis L.), and carp (Cyprinus carpio). In vivo treatment of carp with a high dose of Cd{sup 2+} (10 mg kg{sup -1}, for 3 days) caused a strong inhibition of 7-ethoxyresorufin-O-deethylase (EROD) and a lower inhibition of 7-ethoxycoumarin-O-deethylase (ECOD) activity. The low-dose cadmium treatment (2 mg kg{sup -1} Cd{sup 2+}, for 6+3 days) resulted in 4-fold increase in EROD and a 3-fold increase in ECOD activity. The combined treatment with Cd{sup 2+} and {beta}-NF in both cases led to a loss of EROD inducibility. The silver carp and wels were treated with 10 mg L{sup -1} Cd{sup 2+} for 72 h in water. The Cyt P450 content in the wels liver microsomes was increased significantly after treatment for 48 h, whereas there was only a slight, not significant increase in Cyt P450 content in the silver carp microsomes. While the Cd{sup 2+} treatment resulted in inhibition of the CYP1A isoenzymes (EROD and ECOD), the APND (aminopyrene-N-demethylase, CYP2B or CYP3A isoenzyme) activity was increased 3- to 4-fold in both fish species. In vitro experiments of the effect of Cd{sup 2+} led to a concentration-dependent inhibition in all three investigated fish species. The ECOD isoenzyme of silver carp was the most sensitive to Cd{sup 2+}. The lowest concentration of Cd{sup 2+} resulted in 50% inhibition. The APND isoenzyme was similarly sensitive to Cd{sup 2+} in all three investigated fish species. The most sensitive species was the wels, and the least sensitive were the carp isoenzyme. FTIR spectroscopy confirmed that cadmium caused damage to the protein structure. These results support the enzyme activity measurements measured in vivo and in vitro. (orig.)

  12. Transfer of the cytochrome P450-dependent dhurrin pathway from Sorghum bicolor into Nicotiana tabacum chloroplasts for light-driven synthesis

    Gnanasekaran, Thiyagarajan; Karcher, Daniel; Nielsen, Agnieszka Janina Zygadlo

    2016-01-01

    . For this purpose, we stably engineered the dhurrin pathway from Sorghum bicolor into the chloroplasts of Nicotiana tabacum (tobacco). Dhurrin is a cyanogenic glucoside and its synthesis from the amino acid tyrosine is catalysed by two membrane-bound cytochrome P450 enzymes (CYP79A1 and CYP71E1) and a soluble...... glucosyltransferase (UGT85B1), and is dependent on electron transfer from a P450 oxidoreductase. The entire pathway was introduced into the chloroplast by integrating CYP79A1, CYP71E1, and UGT85B1 into a neutral site of the N. tabacum chloroplast genome. The two P450s and the UGT85B1 were functional when expressed...... compared to 6% in sorghum. The results obtained pave the way for plant P450s involved in the synthesis of economically important compounds to be engineered into the thylakoid membrane of chloroplasts, and demonstrate that their full catalytic cycle can be driven directly by photosynthesis-derived electrons....

  13. 12(R)-hydroxyicosatetraenoic acid: a cytochrome P450-dependent arachidonate metabolite that inhibits Na+, K+-ATPase in the cornea

    Schwartzman, M.L.; Balazy, M.; Masferrer, J.; Abraham, N.G.; McGiff, J.C.; Murphy, R.C.

    1987-01-01

    When corneal microsomes were incubated with arachidonic acid in the presence of an NADPH-generating system, four polar metabolites (compounds A-D) were formed. Synthesis of these metabolites could be inhibited by carbon monoxide, SKF 525A, and anti-cytochrome c reductase antibodies. One of the metabolites, compound C, was found to inhibit partially purified Na + , K + -ATPase from the corneal epithelium in a dose-dependent manner. After compound C was purified by TLC and HPLC, it was found to have a UV absorption spectrum with a maximum absorbance at 236 nm suggesting the presence of a conjugated diene. Mass spectrometric analysis using positive- and negative-ionization modes was carried out on derivatized compound C. Abundant fragment ions were consistent with compound C being a monooxygenated derivative of arachidonic acid with a hydroxyl substituent at carbon-12 of the icosanoid backbone; all deuterium atoms from [ 2 H 8 ]arachidonate were retained in the structure. Compound C was characterized as a 12-hydroxyicosatetraenoic acid. However, only 12(R) isomer was found to be an inhibitor of the Na + , K + -ATPase from the corneal epithelium, suggesting that the biologically active compound C was 12(R)-hydroxyy-5,8,10,14-icosatetraenoic acid. Such an inhibitor of Na + , K + -ATPase synthesized in the cornea may have an important role in regulating ocular transparency and aqueous human secretion

  14. 12(R)-hydroxyicosatetraenoic acid: a cytochrome P450-dependent arachidonate metabolite that inhibits Na/sup +/, K/sup +/-ATPase in the cornea

    Schwartzman, M.L.; Balazy, M.; Masferrer, J.; Abraham, N.G.; McGiff, J.C.; Murphy, R.C.

    1987-11-01

    When corneal microsomes were incubated with arachidonic acid in the presence of an NADPH-generating system, four polar metabolites (compounds A-D) were formed. Synthesis of these metabolites could be inhibited by carbon monoxide, SKF 525A, and anti-cytochrome c reductase antibodies. One of the metabolites, compound C, was found to inhibit partially purified Na/sup +/, K/sup +/-ATPase from the corneal epithelium in a dose-dependent manner. After compound C was purified by TLC and HPLC, it was found to have a UV absorption spectrum with a maximum absorbance at 236 nm suggesting the presence of a conjugated diene. Mass spectrometric analysis using positive- and negative-ionization modes was carried out on derivatized compound C. Abundant fragment ions were consistent with compound C being a monooxygenated derivative of arachidonic acid with a hydroxyl substituent at carbon-12 of the icosanoid backbone; all deuterium atoms from (/sup 2/H/sub 8/)arachidonate were retained in the structure. Compound C was characterized as a 12-hydroxyicosatetraenoic acid. However, only 12(R) isomer was found to be an inhibitor of the Na/sup +/, K/sup +/-ATPase from the corneal epithelium, suggesting that the biologically active compound C was 12(R)-hydroxyy-5,8,10,14-icosatetraenoic acid. Such an inhibitor of Na/sup +/, K/sup +/-ATPase synthesized in the cornea may have an important role in regulating ocular transparency and aqueous human secretion.

  15. Effects of UV light alone and in combination with phenobarbital on bilirubin concentration in serum and on bromosulfophthalein elimination from blood as well as cytochrome P 450-dependent biotransformation reactions in rats

    Ankermann, K.J.; Klinger, W.; Mueller, D.

    1979-01-01

    In studying the effects of UV light alone and combined with the phenobarbital inductor, a shortening of the barbital and hexobarbital lateral position time, a lowering of the bilirubin concentration and an acceleration of the bromosulfophthalein (BSP) clearance could be revealed. Effects not accompanied with an increase of biotransformation reactions such as cytochrome P 450 concentration in liver microsomes and binding of BSP on cytoplasmic acceptor proteins Y and Z of the liver as well as the amidopyridine N demethylation remained unchanged

  16. Challenges and pitfalls of P450-dependent (+)-valencene bioconversion by Saccharomyces cerevisiae.

    Gavira, Carole; Höfer, René; Lesot, Agnès; Lambert, Fanny; Zucca, Joseph; Werck-Reichhart, Danièle

    2013-07-01

    Natural nootkatone is a high value ingredient for the flavor and fragrance industry because of its grapefruit flavor/odor, low sensorial threshold and low availability. Valencene conversion into nootkatol and nootkatone is known to be catalyzed by cytochrome P450 enzymes from both prokaryotic and eukaryotic organisms, but so far development of a viable bioconversion process using either native microorganisms or recombinant enzymes was not successful. Using an in silico gene-mining approach, we selected 4 potential candidate P450 enzymes from higher plants and identified two of them that selectively converted (+)-valencene into β-nootkatol with high efficiency when tested using recombinant yeast microsomes in vitro. Recombinant yeast expressing CYP71D51v2 from tobacco and a P450 reductase from arabidopsis was used for optimization of a bioconversion process. Bioconversion assays led to production of β-nootkatol and nootkatone, but with low yields that decreased upon increase of the substrate concentration. The reasons for this low bioconversion efficiency were further investigated and several factors potentially hampering industry-compatible valencene bioconversion were identified. One is the toxicity of the products for yeast at concentrations exceeding 100 mg L⁻¹. The second is the accumulation of β-nootkatol in yeast endomembranes. The third is the inhibition of the CYP71D51v2 hydroxylation reaction by the products. Furthermore, we observed that the formation of nootkatone from β-nootkatol is not P450-dependent but catalyzed by a yeast component. Based on these data, we propose new strategies for implementation of a viable P450-based bioconversion process. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Control by substrate of the cytochrome p450-dependent redox machinery: mechanistic insights.

    Hlavica, Peter

    2007-08-01

    Based on initial studies with bacterial CYP101A1, a popular concept emerged predicting that substrate-induced low-to-high spin conversion of P450s is universally associated with shifts of the midpoint potential to a more positive value to maximize rates of electron transfer and metabolic turnover. However, evaluation of the plethora of observations with pro- and eukaryotic hemoproteins suggests a caveat as to generalization of this principle. Thus, some P450s are inherently high-spin, so that there is no need for a supportive substrate-triggered impulse to electron flow. With other enzymes, high-spin content is not consonant with reductive activity, and spin transition as such is not essential to sustaining substrate oxidation. Also, with certain proteins the low-spin conformer is reduced as swift as the high-spin entity. Moreover, there is not regularly a linear relationship between high-spin level and anodic shift of the reduction potential. Similarly, in given cases turnover may proceed despite insignificant or even lacking substrate-provoked alterations in the redox behaviour. Thus, folding of the disparate and sometimes conflicting data into a harmonized overall picture is a lingering problem. Apart from direct perturbation of the electrochemical properties, substrate docking may entail changes in enzyme conformation such as to favour productive complexation with redox partners or modulate electron transfer conduits within preformed donor/acceptor adducts, resulting in elevated ease of flow of reducing equivalents. Substrate-steered ordering of the oligomeric aggregation state of P450s is likely to impose steric constraints on heterodimers, causing one component to more readily align with electron carriers. Careful uncovering of electrochemical mechanisms in these systems will be fruitful to tailoring of novel bioenergetic machines and redox chains via redox-inspired protein engineering or molecular Lego, capable of generating products of interest or degrading toxic pollutants. Finally, availability of P450 nanobiochips for high-throughput screening of substrate libraries might expedite drug development.

  18. The influence of single application of paracetamol and/or N-acetylcysteine on rats subchronic exposed to trichloroethylene vapours. I. Effect on hepatic moonooxygenase system dependent of cytochrome P450

    Andrzej Plewka

    2012-06-01

    Full Text Available Background: There is a number of factors which potentially affect occurrence of toxic change in liver after overdosing of paracetamol. Hepatic metabolism of trichloroethylene has primary impact on hepatotoxic effect of this solvent. This means that the combined exposure to these xenobiotics can be particularly harmful for human. The influence of N-acetylcysteine (NAC as a protective factor after paracetamol intoxication was studies. Materials and method: Tests were carried out on rats which were treated with trichloroethylene, paracetamol and/or N-acetylcysteine. In the hepatic microsomal fraction activity of the components of cytochrome P450- dependent monooxygenases was determined Results: Paracetamol slightly stimulated cytochrome P450 having no effect on reductase activity cooperating with it. Cytochrome b5 and its reductase were inhibited by this compound. Trichloroethylene was the inhibitor of compounds of II microsomal electron transport chain. N-acetylcysteine inhibited activity of reductase of NADH-cytochrome b5. Conclusions: Tested doses of the xenobiotics influenced on II microsomal electron transport chain. Protective influence of N-acetylcysteine was better if this compound was applied 2 hours after exposure on xenobiotics

  19. Antibodies against human cytochrome P-450db1 in autoimmune hepatitis type II.

    Zanger, U M; Hauri, H P; Loeper, J; Homberg, J C; Meyer, U A

    1988-11-01

    In a subgroup of children with chronic active hepatitis, circulating autoantibodies occur that bind to liver and kidney endoplasmic reticulum (anti-liver/kidney microsome antibody type I or anti-LKM1). Anti-LKM1 titers follow the severity of the disease and the presence of these antibodies serves as a diagnostic marker for this autoimmune hepatitis type II. We demonstrate that anti-LKM1 IgGs specifically inhibit the hydroxylation of bufuralol in human liver microsomes. Using two assay systems with different selectivity for the two cytochrome P-450 isozymes catalyzing bufuralol metabolism in human liver, we show that anti-LKM1 exclusively recognizes cytochrome P-450db1. Immunopurification of the LKM1 antigen from solubilized human liver microsomes resulted in an electrophoretically homogenous protein that had the same molecular mass (50 kDa) as purified P-450db1 and an identical N-terminal amino acid sequence. Recognition of both purified P-450db1 and the immunoisolated protein on western blots by several monoclonal antibodies confirmed the identity of the LKM1 antigen with cytochrome P-450db1. Cytochrome P-450db1 has been identified as the target of a common genetic polymorphism of drug oxidation. However, the relationship between the polymorphic cytochrome P-450db1 and the appearance of anti-LKM1 autoantibodies as well as their role in the pathogenesis of chronic active hepatitis remains speculative.

  20. Metabolism and binding of cyclophosphamide and its metabolite acrolein to rat hepatic microsomal cytochrome P-450

    Marinello, A.J.; Bansal, S.K.; Paul, B.; Koser, P.L.; Love, J.; Struck, R.F.; Gurtoo, H.L.

    1984-01-01

    The hepatic cytochrome P-450-mediated metabolism and metabolic activation of [chloroethyl-3H]cyclophosphamide [( chloroethyl-3H]CP) and [4-14C]cyclophosphamide [( 4-14C]CP) were investigated in vitro in the reconstituted system containing cytochrome P-450 isolated from phenobarbital-treated rats. In addition, hepatic microsomal binding and the hepatic microsome-mediated metabolism of [14C]acrolein, a metabolite of [4-14C]CP, were also investigated. The metabolism of [chloroethyl-3H]CP and [4-14C]CP to polar metabolites was found to depend on the presence of NADPH and showed concentration dependence with respect to cytochrome P-450 and NADPH:cytochrome P-450 reductase. Km and Vmax values were essentially similar. The patterns of inhibition by microsomal mixed-function oxidase inhibitors, anti-cytochrome P-450 antibody, and heat denaturation of the cytochrome P-450 were essentially similar, with subtle differences between [4-14C]CP and [chloroethyl-3H]CP metabolism. The in vitro metabolic activation of CP in the reconstituted system demonstrated predominant binding of [chloroethyl-3H]CP to nucleic acids and almost exclusive binding of [4-14C]CP to proteins. Gel electrophoresis-fluorography of the proteins in the reconstituted system treated with [4-14C]CP demonstrated localization of the 14C label in the cytochrome P-450 region. To examine this association further, hepatic microsomes were modified with [14C]acrolein in the presence and the absence of NADPH. The results confirmed covalent association between [14C]acrolein and cytochrome P-450 in the microsomes and also demonstrated further metabolism of [14C]acrolein, apparently to an epoxide, which is capable of binding covalently to proteins. The results of these investigations not only confirm the significance of primary metabolism but also emphasize the potential role of the secondary metabolism of cyclophosphamide in some of its toxic manifestations

  1. Posttranslational modification of hepatic cytochrome P-450. Phosphorylation of phenobarbital-inducible P-450 forms PB-4 (IIB1) and PB-5 (IIB2) in isolated rat hepatocytes and in vivo

    Koch, J.A.; Waxman, D.J.

    1989-01-01

    Phosphorylation of hepatic cytochrome P-450 was studied in isolated hepatocytes incubated in the presence of agents known to stimulate protein kinase activity. Incubation of hepatocytes isolated from phenobarbital-induced adult male rats with [ 32 P]orthophosphate in the presence of N 6 , O 2' -dibutyryl-cAMP (diBtcAMP) or glucagon resulted in the phosphorylation of microsomal proteins that are immunoprecipitable by polyclonal antibodies raised to the phenobarbital-induced P-450 form PB-4 (P-450 gene IIB1). Two-dimensional gel electrophoresis revealed that these 32 P-labeled microsomal proteins consist of a mixture of P-450 PB-4 and the closely related P-450 PB-5 (gene IIB2), both of which exhibited heterogeneity in the isoelectric focusing dimension. Phosphorylation of both P-450 forms was markedly enhanced by diBtcAMP at concentrations as low as 5 μM. Phosphoamino acid analysis of the 32 P-labeled P-450 PB-4 + PB-5 immunoprecipitate revealed that these P-450s are phosphorylated on serine in the isolated hepatocytes. Peptide mapping indicated that the site of phosphorylation in hepatocytes is indistinguishable from the site utilized by cAMP-dependent protein kinase in vitro, which was previously identified as serine-128 for the related rabbit protein P-450 LM2. In vitro analyses revealed that phosphorylation of P-450 PB-4 leads to a loss of monooxygenase activity, suggesting that the posttranslational modification of this P-450 enzyme by cAMP-dependent protein kinase may play a role in the modulation of P-450-dependent monooxygenase activity in vivo

  2. Carbonated soft drinks alter hepatic cytochrome P450 isoform expression in Wistar rats.

    Alkhedaide, Adel; Soliman, Mohamed Mohamed; Ibrahim, Zein Shaban

    2016-11-01

    The aim of the current study was to examine the effects of chronic consumption of soft drinks (SDs) on hepatic oxidative stress and cytochrome P450 enzymes (CYPs) expression in the livers of Wistar rats. For 3 consecutive months, the rats had free access to three different soft drinks, Coca-Cola, Pepsi-Cola and 7-UP. The rats were subsequently compared with control group rats that had consumed water. Blood and hepatic tissue samples were assayed for the changes in antioxidants, liver function biomarkers and hepatic gene expression for different isoforms of hepatic CYP. The results indicated that SD consumption (SDC) decreased serum antioxidant levels and increased malondialdehyde secretion, and increased liver biomarkers (glutamate pyruvate transaminase and glutamate oxaloacetate). SD induced alterations in mRNA expression of hepatic antioxidants and cytochrome isoforms. The expression of peroxidase, catalase, CYP1A2, CYP3A2 and CYP2C11 in the liver were upregulated following SDC. By contrast, CYP2B1 was downregulated after 3 months of SDC in liver tissue samples. Thus, the present findings indicate that SDs induced oxidative stress in the liver of Wistar rats and for the first time, to the best of our knowledge, indicate that SDC disrupts hepatic CYP enzymes that may affect drug metabolism. Therefore, drug-dosing programs should be carefully designed to take these novel findings into consideration for the treatment of diseases.

  3. Role of active oxygen species in the photodestruction of microsomal cytochrome P-450 and associated monooxygenases by hematoporphyrin derivative in rats

    Das, M.; Dixit, R.; Mukhtar, H.; Bickers, D.R.

    1985-01-01

    The cytochrome P-450 in hepatic microsomes prepared from rats pretreated with hematoporphyrin derivative was shown to be rapidly destroyed in the presence of long-wave ultraviolet light. The photocatalytic destruction of the heme-protein was dependent on both the dose of ultraviolet light and of hematoporphyrin derivative administered to the animals. The destructive reaction was accompanied by increased formation of cytochrome P-420, loss of microsomal heme content, and diminished catalytic activity of cytochrome P-450-dependent monooxygenases such as aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase. The specificity of the effect on cytochrome P-450 was confirmed by the observation that other heme-containing moieties such as myoglobin and cytochrome c were not susceptible to photocatalytic destruction. The destruction of cytochrome P-450 was a photodynamic process requiring oxygen since quenchers of singlet oxygen, including 2,5-dimethylfuran, histidine, and beta-carotene, each substantially diminished the reaction. Scavengers of superoxide anion such as superoxide dismutase and of H 2 O 2 such as catalase did not protect against photodestruction of cytochrome P-450, whereas inhibitors of the hydroxyl radical, including benzoate, mannitol, and ethyl alcohol, did afford protection. These results indicate that lipid-rich microsomal membranes and the heme-protein cytochrome P-450 embedded therein are potential targets of injury in cells exposed to hematoporphyrin derivative photosensitization

  4. Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism

    Gates, Simon; Miners, John O

    1999-01-01

    Aims The plasma clearance of theobromine (TB; 3,7-dimethylxanthine) is known to be induced in cigarette smokers. To determine whether TB may serve as a model substrate for cytochrome P450 (CYP) 1A2, or possibly other isoforms, studies were undertaken to identify the individual human liver microsomal CYP isoforms responsible for the conversion of TB to its primary metabolites. Methods The kinetics of formation of the primary TB metabolites 3-methylxanthine (3-MX), 7-methylxanthine (7-MX) and 3,7-dimethyluric acid (3,7-DMU) by human liver microsomes were characterized using a specific hplc procedure. Effects of CYP isoform-selective xenobiotic inhibitor/substrate probes on each pathway were determined and confirmatory studies with recombinant enzymes were performed to define the contribution of individual isoforms to 3-MX, 7-MX and 3,7-DMU formation. Results The CYP1A2 inhibitor furafylline variably inhibited (0–65%) 7-MX formation, but had no effect on other pathways. Diethyldithiocarbamate and 4-nitrophenol, probes for CYP2E1, inhibited the formation of 3-MX, 7-MX and 3,7-DMU by ≈55–60%, 35–55% and 85%, respectively. Consistent with the microsomal studies, recombinant CYP1A2 and CYP2E1 exhibited similar apparent Km values for 7-MX formation and CYP2E1 was further shown to have the capacity to convert TB to both 3-MX and 3,7-DMU. Conclusions Given the contribution of multiple isoforms to 3-MX and 7-MX formation and the negligible formation of 3,7-DMU in vivo, TB is of little value as a CYP isoform-selective substrate in humans. PMID:10215755

  5. Vinclozolin modulates hepatic cytochrome P450 isoforms during pregnancy.

    de Oca, Félix Genoveva García-Montes; López-González, Ma de Lourdes; Escobar-Wilches, Derly Constanza; Chavira-Ramírez, Roberto; Sierra-Santoyo, Adolfo

    2015-06-01

    Vinclozolin (V) is classified as a potent endocrine disruptor. The aim of the present study was to determine the effects of V on rat liver CYP regulation and on serum levels of testosterone and estradiol during pregnancy. Pregnancy decreased the liver total CYP content by 65%, enzyme activities of MROD, PROD, and PNPH, and testosterone hydroxylation activities, as well as the protein content of CYP2A and 3A. V exposure remarkably induced the protein content and enzyme activities of CYP1A, 2A, 2B and 3A subfamilies. Testosterone and estradiol were affected in an opposite manner, provoking a 3.5-fold increase in the estradiol/testosterone ratio. These results suggest that V could regulate the hepatic CYP expression through interaction with receptors and coactivators involved in its expression and may play an important role in hormonal balance during pregnancy. In addition, the results may also contribute to understanding the toxicity of V by in utero exposure. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Lack of evidence for metabolism of p-phenylenediamine by human hepatic cytochrome P450 enzymes

    Stanley, Lesley A.; Skare, Julie A.; Doyle, Edward; Powrie, Robert; D'Angelo, Diane; Elcombe, Clifford R.

    2005-01-01

    p-Phenylenediamine (PPD) is a widely used ingredient in permanent hair dyes; however, little has been published on its metabolism, especially with respect to hepatic cytochrome P450 (CYP)-mediated oxidation. This is regarded as a key step in the activation of carcinogenic arylamines that ultimately leads to the development of bladder cancer. Most epidemiology studies show no significant association between personal use of hair dyes and bladder cancer, but one recent study reported an increased risk of bladder cancer in women who were frequent users of permanent hair dyes. The aim of the present study was to use intact human hepatocytes, human liver microsomes, and heterologously expressed human CYPs to determine whether PPD is metabolised by hepatic CYPs to form an N-hydroxylamine. p-Phenylenediamine was N-acetylated by human hepatocytes to form N-acetylated metabolites, but there was no evidence for the formation of mono-oxygenated metabolites or for enzyme-mediated covalent binding of 14 C-PPD to microsomal protein. In contrast, 2-aminofluorene underwent CYP-mediated metabolism to ≥4 different hydroxylated metabolites. The lack of evidence for hepatic CYP-mediated metabolism of PPD is inconsistent with the hypothesis that this compound plays a causal role in the development of bladder cancer via a mode of action involving hepatic metabolism to an N-hydroxyarylamine

  7. Blarina brevicauda as a biological monitor of polychlorinated biphenyls: evaluation of hepatic cytochrome P450 induction.

    Russell, Julie S; Halbrook, Richard S; Woolf, Alan; French, John B; Melancon, Mark J

    2004-08-01

    We assessed the value of short-tailed shrews (Blarina brevicauda) as a possible biomonitor for polychlorinated biphenyl pollution through measurement of the induction of hepatic cytochrome P450 and associated enzyme activities. First, we checked the inducibility of four monooxygenases (benzyloxyresorufin-O-dealkylase [BROD], ethoxyresorufin-O-dealkylase [EROD], methoxyresorufin-O-dealkylase [MROD], and pentoxyresorufin-O-dealkylase [PROD]) by measuring the activity of these enzymes in hepatic microsomes prepared from shrews injected with beta-naphthoflavone (betaNF) or phenobarbital (PB), typical inducers of cytochrome P4501A (CYP1A) and CYP2B enzyme families, respectively. Enzyme activity was induced in shrews that received betaNF but not in shrews that received PB; PROD was not induced by either exposure. Later, shrews were exposed to a mixture of polychlorinated biphenyls (PCBs) (Aroclor 1242:1254, in 1:2 ratio) at 0.6, 9.6, and 150 ppm in food, for 31 d. Induction in these shrews was measured by specific enzyme activity (BROD, EROD, and MROD) in hepatic microsomes, by western blotting of solubilized microsomes against antibodies to CYP1A or CYP2B, and by duration of sodium pentobarbital-induced sleep. These three CYP enzymes were induced in shrews by PCBs at similar levels of exposure as in cotton rat (Sigmodon hispidus). Neither sleep time nor the amount of CYP2B family protein were affected by PCB exposure. Blarina brevicauda can be a useful biomonitor of PCBs that induce CYP1A, especially in habitats where they are the abundant small mammal.

  8. Regulation of Porcine Hepatic Cytochrome P450 — Implication for Boar Taint

    Martin Krøyer Rasmussen

    2014-09-01

    Full Text Available Cytochrome P450 (CYP450 is the major family of enzymes involved in the metabolism of several xenobiotic and endogenous compounds. Among substrates for CYP450 is the tryptophan metabolite skatole (3-methylindole, one of the major contributors to the off-odour associated with boar-tainted meat. The accumulation of skatole in pigs is highly dependent on the hepatic clearance by CYP450s. In recent years, the porcine CYP450 has attracted attention both in relation to meat quality and as a potential model for human CYP450. The molecular regulation of CYP450 mRNA expression is controlled by several nuclear receptors and transcription factors that are targets for numerous endogenously and exogenously produced agonists and antagonists. Moreover, CYP450 expression and activity are affected by factors such as age, gender and feeding. The regulation of porcine CYP450 has been suggested to have more similarities with human CYP450 than other animal models, including rodents. This article reviews the available data on porcine hepatic CYP450s and its implications for boar taint.

  9. A human cytochrome P-450 is recognized by anti-liver/kidney microsome antibodies in autoimmune chronic hepatitis.

    Kiffel, L; Loeper, J; Homberg, J C; Leroux, J P

    1989-02-28

    1- Anti-liver/kidney microsome autoantibodies type 1 (anti-LKM1), observed in some children with chronic active hepatitis, were used to isolate their antigen in human liver microsomes. A protein, called P-LKM1 was thus purified. This protein was recognized by a rabbit antiserum directed against the related human cytochromes P-450 bufI and P-450 bufII. 2- A human liver microsomal protein immunoprecipitated with anti-LKM1 sera was also recognized by anti cytochromes P-450 bufI/II antibodies. 3- Anti-LKM1 antibodies potently inhibited microsomal bufuralol 1'-hydroxylation. These results displayed the possible identity between cytochrome P-450 bufI/II and LKM1 antigen.

  10. Responsiveness of cerebral and hepatic cytochrome P450s in rat offspring prenatally exposed to lindane

    Johri, Ashu; Yadav, Sanjay; Dhawan, Alok; Parmar, Devendra

    2008-01-01

    ABSTRACT: Prenatal exposure to low doses of lindane has been shown to affect the ontogeny of xenobiotic metabolizing cytochrome P450s (CYPs), involved in the metabolism and neurobehavioral toxicity of lindane. Attempts were made in the present study to investigate the responsiveness of CYPs in offspring prenatally exposed to lindane (0.25 mg/kg b. wt.; 1/350th of LD 50 ; p. o. to mother) when challenged with 3-methylcholanthrene (MC) or phenobarbital (PB), inducers of CYP1A and 2B families or a sub-convulsant dose of lindane (30 mg/kg b. wt., p. o.) later in life. Prenatal exposure to lindane was found to produce an increase in the mRNA and protein expression of CYP1A1, 1A2, 2B1, 2B2 isoforms in brain and liver of the offspring at postnatal day 50. The increased expression of the CYPs in the offspring suggests the sensitivity of the CYPs during postnatal development, possibly, to low levels of lindane, which may partition into mother's milk. A higher increase in expression of CYP1A and 2B isoenzymes and their catalytic activity was observed in animals pretreated prenatally with lindane and challenged with MC (30 mg/kg, i. p. x 5 days) or PB (80 mg/kg, i. p. x 5 days) when young at age (approx. 7 weeks) compared to animals exposed to MC or PB alone. Further, challenge of the control and prenatally exposed offspring with a single sub-convulsant dose of lindane resulted in an earlier onset and increased incidence of convulsions in the offspring prenatally exposed to lindane have demonstrated sensitivity of the CYPs in the prenatally exposed offspring. Our data assume significance as the subtle changes in the expression profiles of hepatic and cerebral CYPs in rat offspring during postnatal development could modify the adult response to a later exposure to xenobiotics

  11. Early postoperative erythromycin breath test correlates with hepatic cytochrome P4503A activity in liver transplant recipients

    Schmidt, L E; Olsen, A K; Stentoft, K

    2001-01-01

    BACKGROUND: Interindividual variation in the pharmacokinetics of the immunosuppressive agents cyclosporine (INN, ciclosporin) and tacrolimus may result from differences in the activity of cytochrome P4503A (CYP3A). The erythromycin breath test is an in vivo assay of hepatic CYP3A activity......, but the method has never been directly validated. The aim of the study was to investigate whether an early postoperative erythromycin breath test correlated with the hepatic CYP3A protein level and catalytic activity in liver transplant recipients. METHODS: In 18 liver transplant recipients, the erythromycin...... breath test was performed within 2 hours after transplantation. A graft biopsy was obtained during surgery and analyzed for the CYP3A protein level by Western blotting and for CYP3A activity with erythromycin demethylation and testosterone 6beta- hydroxylation assays. RESULTS: The erythromycin breath...

  12. Suppression of cytochrome P450 reductase (POR) expression in hepatoma cells replicates the hepatic lipidosis observed in hepatic POR-null mice.

    Porter, Todd D; Banerjee, Subhashis; Stolarczyk, Elzbieta I; Zou, Ling

    2011-06-01

    Cytochrome P450 reductase (POR) is a microsomal electron transport protein essential to cytochrome P450-mediated drug metabolism and sterol and bile acid synthesis. The conditional deletion of hepatic POR gene expression in mice results in a marked decrease in plasma cholesterol levels counterbalanced by the accumulation of triglycerides in lipid droplets in hepatocytes. To evaluate the role of cholesterol and bile acid synthesis in this hepatic lipidosis, as well as the possible role of lipid transport from peripheral tissues, we developed a stable, small interfering RNA (siRNA)-mediated cell culture model for the suppression of POR. POR mRNA and protein expression were decreased by greater than 50% in McArdle-RH7777 rat hepatoma cells 10 days after transfection with a POR-siRNA expression plasmid, and POR expression was nearly completely extinguished by day 20. Immunofluorescent analysis revealed a marked accumulation of lipid droplets in cells by day 15, accompanied by a nearly 2-fold increase in cellular triglyceride content, replicating the lipidosis seen in hepatic POR-null mouse liver. In contrast, suppression of CYP51A1 (lanosterol demethylase) did not result in lipid accumulation, indicating that loss of cholesterol synthesis is not the basis for this lipidosis. Indeed, addition of cholesterol to the medium appeared to augment the lipidosis in POR-suppressed cells, whereas removal of lipids from the medium reversed the lipidosis. Oxysterols did not accumulate in POR-suppressed cells, discounting a role for liver X receptor in stimulating triglyceride synthesis, but addition of chenodeoxycholate significantly repressed lipid accumulation, suggesting that the absence of bile acids and loss of farnesoid X receptor stimulation lead to excessive triglyceride synthesis.

  13. Antibodies against human cytochrome P-450db1 in autoimmune hepatitis type II.

    Zanger, U M; Hauri, H P; Loeper, J; Homberg, J C; Meyer, U A

    1988-01-01

    In a subgroup of children with chronic active hepatitis, circulating autoantibodies occur that bind to liver and kidney endoplasmic reticulum (anti-liver/kidney microsome antibody type I or anti-LKM1). Anti-LKM1 titers follow the severity of the disease and the presence of these antibodies serves as a diagnostic marker for this autoimmune hepatitis type II. We demonstrate that anti-LKM1 IgGs specifically inhibit the hydroxylation of bufuralol in human liver microsomes. Using two assay systems...

  14. Feed-drug interaction of orally applied butyrate and phenobarbital on hepatic cytochrome P450 activity in chickens.

    Mátis, G; Kulcsár, A; Petrilla, J; Hermándy-Berencz, K; Neogrády, Zs

    2016-08-01

    The expression of hepatic drug-metabolizing cytochrome P450 (CYP) enzymes may be affected by several nutrition-derived compounds, such as by the commonly applied feed additive butyrate, possibly leading to feed-drug interactions. The aim of this study was to provide some evidence if butyrate can alter the activity of hepatic CYPs in chickens exposed to CYP-inducing xenobiotics, monitoring for the first time the possibility of such interaction. Ross 308 chickens in the grower phase were treated with daily intracoelomal phenobarbital (PB) injection (80 mg/kg BW), applied as a non-specific CYP-inducer, simultaneously with two different doses of intra-ingluvial sodium butyrate boluses (0.25 and 1.25 g/kg BW) for 5 days. Activity of CYP2H and CYP3A subfamilies was assessed by specific enzyme assays from isolated liver microsomes. According to our results, the lower dose of orally administered butyrate significantly attenuated the PB-triggered elevation of both hepatic CYP2H and CYP3A activities, which might be in association with the partly common signalling pathways of butyrate and CYP-inducing drugs, such as that of PB. Based on these data, butyrate may take part in pharmacoepigenetic interactions with simultaneously applied drugs or other CYP-inducing xenobiotics, with possible consequences for food safety and pharmacotherapy. Butyrate was found to be capable to maintain physiological CYP activity by attenuating CYP induction, underlining the safety of butyrate application in poultry nutrition. Journal of Animal Physiology and Animal Nutrition © 2015 Blackwell Verlag GmbH.

  15. Inhibitory effects of cytostatically active 6-aminobenzo[c]phenanthridines on cytochrome P450 enzymes in human hepatic microsomes.

    Zebothsen, Inga; Kunze, Thomas; Clement, Bernd

    2006-07-01

    Besides assays for the evaluation of efficacy new drug candidates have to undergo extensive testings for enhancement of pharmaceutical drug safety and optimization of application. The objective of the present work was to investigate the pharmacokinetic drug drug interaction potential for the cytostatically active 6-aminobenzo[c]phenanthridines BP-11 (6-amino-11,12-dihydro-11-(4-hydroxy-3,5-dimethoxyphenyl)benzo[c]phenanthridine) and BP-D7 (6-amino-11-(3,4,5-trimethoxyphenyl)benzo[c]phenanthridine) in vitro through incubation with human hepatic microsomes and marker substrates. For these studies the cytochrome P-450 isoenzymes and corresponding marker substrates recommended by the EMEA (The European Agency for the Evaluation of Medicinal Products) were chosen. In detail these selective substrates were caffeine (CYP1A2), coumarin (CYP2A6), tolbutamide (CYP2C9), S-(+)-mephenytoin (CYP2C19), dextromethorphane (CYP2D6), chlorzoxazone (CYP2E1) and testosterone (CYP3A4). Incubations with each substrate were carried out without a possible inhibitor and in the presence of a benzo[c]phenanthridine or a selective inhibitor at varying concentrations. Marker activities were determined by HPLC (high performance liquid chromatography). For the isoenzymes showing more than 50% inhibition by the addition of 20 microM BP-11 or BP-D7 additional concentrations of substrate and inhibitor were tested for a characterization of the inhibition. The studies showed a moderate risk for BP-11 for interactions with the cytochrome P-450 isoenzymes CYP1A2, CYP2C9, CYP2D6 and CYP3A4. BP-D7, the compound with the highest cytotstatic efficacy, showed only a moderate risk for interactions with drugs, also metabolized by CYP3A4.

  16. Effect of p-amino-diphenyl ethers on hepatic microsomal cytochrome P450.

    Jiang, Huidi; Xuan, Guida

    2003-09-01

    The present paper aims to investigate whether p-amino-2',4'-dichlorodiphenyl ether and p-amino-4'-methyldiphenyl ether are inhibitors as well as inducers of P450. Mice were given daily intraperitoneal (ip) injections of p-amino-2',4'-dichlorodiphenyl ether (0.25 mmol/kg) or p-amino-4'-methyldiphenyl ether (0.25 mmol/kg) for 4 days and tested at 24 h and 48 h after the last dose injection. The results showed the mice pentobarbital sleeping time was shorter and the P450 content of hepatic microsome increased significantly in the group pretreated with p-amino-4'-methyldiphenyl ether when compared with the control group, while in mice pretreated with p-amino-2',4'-dichlorodiphenyl ether the hepatic microsome P450 content increased but the pentobarbital sleeping time was extended in clear contrast to the control group. The sleeping time of the phenobarbital group (80 mg/kg daily ip injection for 4 days) was shortened at 24 h after the last injection with increased P450 content of hepatic microsome, but it showed no difference at 48 h. The zoxazolamine-paralysis times of mice treated with p-amino-2',4'-dichlorodiphenyl ether were longer than those of the control mice, while the same dose of zoxazolamine did not lead to paralysis in mice pretreated with BNF. p-Amino-2',4'-dichlorodiphenyl ether and p-amino-4'-methyldiphenyl ether inhibited the activity of 7-ethoxyresorufin O-deethylase from rat hepatic microsome induced by BNF in vitro by 70.0% and 50.1% respectively. These results suggest that p-amino-2',4'-dichlorodiphenyl ether and p-amino-4'-methyldiphenyl ether are inhibitors as well as inducers of P450.

  17. Two azole fungicides (carcinogenic triadimefon and non-carcinogenic myclobutanil) exhibit different hepatic cytochrome P450 activities in medaka fish

    Lin, Chun-Hung [Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan (China); Chou, Pei-Hsin [Department of Environmental Engineering, National Cheng-Kung University, Tainan, Taiwan (China); Chen, Pei-Jen, E-mail: chenpj@ntu.edu.tw [Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan (China)

    2014-07-30

    Highlights: • We assess ecotoxicological impact of azole fungicides in the aquatic environment. • Carcinogenic and non-carcinogenic azoles show different CYP activities in medaka. • We compare azole-induced CYP expression and carcinogenesis between fish and rodents. • Liver CYP-enzyme induction is a key event in conazole-induced tumorigenesis. • We suggest toxicity evaluation methods for azole fungicides using medaka fish. - Abstract: Conazoles are a class of imidazole- or triazole-containing drugs commonly used as fungicides in agriculture and medicine. The broad application of azole drugs has led to the contamination of surface aquifers receiving the effluent of municipal or hospital wastewater or agricultural runoff. Several triazoles are rodent carcinogens; azole pollution is a concern to environmental safety and human health. However, the carcinogenic mechanisms associated with cytochrome P450 enzymes (CYPs) of conazoles remain unclear. We exposed adult medaka fish (Oryzias latipes) to continuous aqueous solutions of carcinogenic triadimefon and non-carcinogenic myclobutanil for 7 to 20 days at sub-lethal or environmentally relevant concentrations and assessed hepatic CYP activity and gene expression associated with CYP-mediated toxicity. Both triadimefon and myclobutanil induced hepatic CYP3A activity, but only triadimefon enhanced CYP1A activity. The gene expression of cyp3a38, cyp3a40, pregnane x receptor (pxr), cyp26b, retinoid acid receptor γ1 (rarγ1) and p53 was higher with triadimefon than myclobutanil. As well, yeast-based reporter gene assay revealed that 4 tested conazoles were weak agonists of aryl hydrocarbon receptor (AhR). We reveal differential CYP gene expression with carcinogenic and non-carcinogenic conazoles in a lower vertebrate, medaka fish. Liver CYP-enzyme induction may be a key event in conazole-induced tumorigenesis. This information is essential to evaluate the potential threat of conazoles to human health and fish

  18. Two azole fungicides (carcinogenic triadimefon and non-carcinogenic myclobutanil) exhibit different hepatic cytochrome P450 activities in medaka fish

    Lin, Chun-Hung; Chou, Pei-Hsin; Chen, Pei-Jen

    2014-01-01

    Highlights: • We assess ecotoxicological impact of azole fungicides in the aquatic environment. • Carcinogenic and non-carcinogenic azoles show different CYP activities in medaka. • We compare azole-induced CYP expression and carcinogenesis between fish and rodents. • Liver CYP-enzyme induction is a key event in conazole-induced tumorigenesis. • We suggest toxicity evaluation methods for azole fungicides using medaka fish. - Abstract: Conazoles are a class of imidazole- or triazole-containing drugs commonly used as fungicides in agriculture and medicine. The broad application of azole drugs has led to the contamination of surface aquifers receiving the effluent of municipal or hospital wastewater or agricultural runoff. Several triazoles are rodent carcinogens; azole pollution is a concern to environmental safety and human health. However, the carcinogenic mechanisms associated with cytochrome P450 enzymes (CYPs) of conazoles remain unclear. We exposed adult medaka fish (Oryzias latipes) to continuous aqueous solutions of carcinogenic triadimefon and non-carcinogenic myclobutanil for 7 to 20 days at sub-lethal or environmentally relevant concentrations and assessed hepatic CYP activity and gene expression associated with CYP-mediated toxicity. Both triadimefon and myclobutanil induced hepatic CYP3A activity, but only triadimefon enhanced CYP1A activity. The gene expression of cyp3a38, cyp3a40, pregnane x receptor (pxr), cyp26b, retinoid acid receptor γ1 (rarγ1) and p53 was higher with triadimefon than myclobutanil. As well, yeast-based reporter gene assay revealed that 4 tested conazoles were weak agonists of aryl hydrocarbon receptor (AhR). We reveal differential CYP gene expression with carcinogenic and non-carcinogenic conazoles in a lower vertebrate, medaka fish. Liver CYP-enzyme induction may be a key event in conazole-induced tumorigenesis. This information is essential to evaluate the potential threat of conazoles to human health and fish

  19. Protection by Nigella sativa against carbon tetrachloride-induced downregulation of hepatic cytochrome P450 isozymes in rats.

    Ibrahim, Zein S; Ishizuka, Mayumi; Soliman, Mohamed; ElBohi, Khlood; Sobhy, Wageh; Muzandu, Kaampwe; Elkattawy, Azza M; Sakamoto, Kentaro Q; Fujita, Shoichi

    2008-11-01

    Nigella sativa (family Ranunculaceae) is an annual plant that has been traditionally used on the Indian subcontinent and in Middle Eastern countries. In this study, we investigated the effect of N. sativa oil on the drug-metabolizing cytochrome P450 (CYP) enzymes and whether it has a protective effect against the acute hepatotoxicity of CCl4. Intraperitoneal injection of rats with CCl4 drastically decreased CYP2E1, CYP2B, CYP3A2, CYP2C11, and CYP1A2 mRNA and protein expressions. Oral administration of 1 ml/kg N. sativa oil every day for one week prior to CCl4 injection alleviated CCl4-induced suppression of CYP2B, CYP3A2, CYP2C11, and CYP1A2. Moreover, CCl4 increased iNOS and TNFalpha mRNA, while N. sativa oil administration for one week prior to CCl4 injection downregulated the CCl4-induced iNOS mRNA and up-regulated IL-10 mRNA. These results indicate that N. sativa oil administration has a protective effect against the CCl4-mediated suppression of hepatic CYPs and that this protective effect is partly due to the downregulation of NO production and up-regulation of the anti-inflammatory IL-10.

  20. Pyrethroid insecticide lambda-cyhalothrin induces hepatic cytochrome P450 enzymes, oxidative stress and apoptosis in rats.

    Martínez, María-Aránzazu; Ares, Irma; Rodríguez, José-Luis; Martínez, Marta; Roura-Martínez, David; Castellano, Victor; Lopez-Torres, Bernardo; Martínez-Larrañaga, María-Rosa; Anadón, Arturo

    2018-08-01

    This study aimed to examine in rats the effects of the Type II pyrethroid lambda-cyhalothrin on hepatic microsomal cytochrome P450 (CYP) isoform activities, oxidative stress markers, gene expression of proinflammatory, oxidative stress and apoptosis mediators, and CYP isoform gene expression and metabolism phase I enzyme PCR array analysis. Lambda-cyhalothrin, at oral doses of 1, 2, 4 and 8mg/kg bw for 6days, increased, in a dose-dependent manner, hepatic activities of ethoxyresorufin O-deethylase (CYP1A1), methoxyresorufin O-demethylase (CYP1A2), pentoxyresorufin O-depentylase (CYP2B1/2), testosterone 7α- (CYP2A1), 16β- (CYP2B1), and 6β-hydroxylase (CYP3A1/2), and lauric acid 11- and 12-hydroxylase (CYP4A1/2). Similarly, lambda-cyhalothrin (4 and 8mg/kg bw, for 6days), in a dose-dependent manner, increased significantly hepatic CYP1A1, 1A2, 2A1, 2B1, 2B2, 2E1, 3A1, 3A2 and 4A1 mRNA levels and IL-1β, NFκB, Nrf2, p53, caspase-3 and Bax gene expressions. PCR array analysis showed from 84 genes examined (P1.5), changes in mRNA levels in 18 genes: 13 up-regulated and 5 down-regulated. A greater fold change reversion than 3-fold was observed on the up-regulated ALDH1A1, CYP2B2, CYP2C80 and CYP2D4 genes. Ingenuity Pathway Analysis (IPA) groups the expressed genes into biological mechanisms that are mainly related to drug metabolism. In the top canonical pathways, Oxidative ethanol degradation III together with Fatty Acid α-oxidation may be significant pathways for lambda-cyhalothrin. Our results may provide further understanding of molecular aspects involved in lambda-cyhalothrin-induced liver injury. Copyright © 2018. Published by Elsevier B.V.

  1. Overexpression of cerebral and hepatic cytochrome P450s alters behavioral activity of rat offspring following prenatal exposure to lindane

    Johri, Ashu; Yadav, Sanjay; Dhawan, Alok [Developmental Toxicology Division, Industrial Toxicology Research Centre, P. O. Box 80, M. G. Marg, Lucknow-226 001, U. P. (India); Parmar, Devendra [Developmental Toxicology Division, Industrial Toxicology Research Centre, P. O. Box 80, M. G. Marg, Lucknow-226 001, U. P. (India)

    2007-12-15

    Oral administration of different doses (0.0625, 0.125 or 0.25 mg/kg corresponding to 1/1400th, 1/700th or 1/350th of LD{sub 50}) of lindane to the pregnant Wistar rats from gestation days 5 to 21 were found to produce a dose-dependent increase in the activity of cytochrome P450 (CYP)-dependent 7-ethoxyresorufin-O-deethylase (EROD), 7-pentoxyresorufin-O-dealkylase (PROD) and N-nitrosodimethylamine demethylase (NDMA-d) in brain and liver of offspring postnatally at 3 weeks. The increase in the activity of CYP monooxygenases was found to be associated with the increase in the mRNA and protein expression of xenobiotic metabolizing CYP1A, 2B and 2E1 isoenzymes in the brain and liver of offspring. Dose-dependent alterations in the parameters of spontaneous locomotor activity in the offspring postnatally at 3 weeks have suggested that increase in CYP activity may possibly lead to the formation of metabolites to the levels that may be sufficient to alter the behavioral activity of the offspring. Interestingly, the inductive effect on cerebral and hepatic CYPs was found to persist postnatally up to 6 weeks in the offspring at the relatively higher doses (0.125 and 0.25 mg/kg) of lindane and up to 9 weeks at the highest dose (0.25 mg/kg), though the magnitude of induction was less than that observed at 3 weeks. Alterations in the parameters of spontaneous locomotor activity in the offspring postnatally at 6 and 9 weeks, though significant only in the offspring at 3 and 6-week of age, have further indicated that due to the reduced activity of the CYPs during the ontogeny, lindane and its metabolites may not be effectively cleared from the brain. The data suggest that low dose prenatal exposure to the pesticide has the potential to produce overexpression of xenobiotic metabolizing CYPs in brain and liver of the offspring which may account for the behavioral changes observed in the offspring.

  2. Overexpression of cerebral and hepatic cytochrome P450s alters behavioral activity of rat offspring following prenatal exposure to lindane

    Johri, Ashu; Yadav, Sanjay; Dhawan, Alok; Parmar, Devendra

    2007-01-01

    Oral administration of different doses (0.0625, 0.125 or 0.25 mg/kg corresponding to 1/1400th, 1/700th or 1/350th of LD 50 ) of lindane to the pregnant Wistar rats from gestation days 5 to 21 were found to produce a dose-dependent increase in the activity of cytochrome P450 (CYP)-dependent 7-ethoxyresorufin-O-deethylase (EROD), 7-pentoxyresorufin-O-dealkylase (PROD) and N-nitrosodimethylamine demethylase (NDMA-d) in brain and liver of offspring postnatally at 3 weeks. The increase in the activity of CYP monooxygenases was found to be associated with the increase in the mRNA and protein expression of xenobiotic metabolizing CYP1A, 2B and 2E1 isoenzymes in the brain and liver of offspring. Dose-dependent alterations in the parameters of spontaneous locomotor activity in the offspring postnatally at 3 weeks have suggested that increase in CYP activity may possibly lead to the formation of metabolites to the levels that may be sufficient to alter the behavioral activity of the offspring. Interestingly, the inductive effect on cerebral and hepatic CYPs was found to persist postnatally up to 6 weeks in the offspring at the relatively higher doses (0.125 and 0.25 mg/kg) of lindane and up to 9 weeks at the highest dose (0.25 mg/kg), though the magnitude of induction was less than that observed at 3 weeks. Alterations in the parameters of spontaneous locomotor activity in the offspring postnatally at 6 and 9 weeks, though significant only in the offspring at 3 and 6-week of age, have further indicated that due to the reduced activity of the CYPs during the ontogeny, lindane and its metabolites may not be effectively cleared from the brain. The data suggest that low dose prenatal exposure to the pesticide has the potential to produce overexpression of xenobiotic metabolizing CYPs in brain and liver of the offspring which may account for the behavioral changes observed in the offspring

  3. Dynamic movement of cytochrome c from mitochondria into cytosol and peripheral circulation in massive hepatic cell injury.

    Kobayashi, Yoshinori; Mori, Masaaki; Naruto, Takuya; Kobayashi, Naoki; Sugai, Toshiyuki; Imagawa, Tomoyuki; Yokota, Shumpei

    2004-12-01

    In the process of apoptosis, it is known that the transition of cytochrome c from mitochondria into the cytosol occurs, and tumor necrosis factor (TNF)-alpha is one of the molecules responsible for this event. But in the state of hypercytokine induced by D-galactosamine (D-GaIN)/Lipopolysaccharide (LPS), the localization of cytochrome c is little known. Rats were administrated with D-GaIN(700 mg/kg)/LPS(200 microg/kg). Blood and tissue samples were collected and examined for levels of pro-inflammatory cytokines, the apoptosis of liver cells, and the localization of cytochrome c. Before administration of D-GaIN/LPS, cytochrome c was definitely localized in the mitochondria. At 2 h after simultaneous administration of D-GaIN/LPS, cytochrome c had accumulated in the cytosol following abrupt increases of plasma TNF-alpha. Massive cell destruction due to apoptosis proved by Terminal deoxynucleo-tidyl transferase-mediated dUTP nick end labeling staining was observed in liver tissue 4 h later and markedly increased levels of cytochrome c were detected in the plasma 12 h after D-GaIN/LPS administration. Liver injury induced by simultaneous administration of D-GaIN/LPS was closely associated with the production of TNF-alpha, and also with the dynamic movement of cytochrome c from the mitochondria into the cytosol, and then into the systemic circulation. The detection of plasma cytochrome c levels may be a useful clinical tool for the detection of apoptosis in vivo.

  4. Rapid and accurate liquid chromatography and tandem mass spectrometry method for the simultaneous quantification of ten metabolic reactions catalyzed by hepatic cytochrome P450 enzymes.

    Shi, Rong; Ma, Bingliang; Wu, Jiasheng; Wang, Tianming; Ma, Yueming

    2015-10-01

    The hepatic cytochrome P450 enzymes play a central role in the biotransformation of endogenous and exogenous substances. A sensitive high-throughput liquid chromatography with tandem mass spectrometry assay was developed and validated for the simultaneous quantification of the products of ten metabolic reactions catalyzed by hepatic cytochrome P450 enzymes. After the substrates were incubated separately, the samples were pooled and analyzed by liquid chromatography with tandem mass spectrometry using an electrospray ionization source in the positive and negative ion modes. The method exhibited linearity over a broad concentration range, insensitivity to matrix effects, and high accuracy, precision, and stability. The novel method was successfully applied to study the kinetics of phenacetin-O deethylation, coumarin-7 hydroxylation, bupropion hydroxylation, taxol-6 hydroxylation, omeprazole-5 hydroxylation, dextromethorphan-O demethylation, tolbutamide-4 hydroxylation, chlorzoxazone-6 hydroxylation, testosterone-6β hydroxylation, and midazolam-1 hydroxylation in rat liver microsomes. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Time course for the modulation of hepatic cytochrome P450 after administration of ethylbenzene and its correlation with toluene metabolism.

    Yuan, W; Sequeira, D J; Cawley, G F; Eyer, C S; Backes, W L

    1997-03-01

    The goal of the present study was to examine the time course for changes in P450 expression and hydrocarbon metabolism after acute treatment with the simple aromatic hydrocarbon ethylbenzene (EB) and to correlate these alterations with the changes observed in alkylbenzene metabolism. Male Holtzman rats were treated with a single intraperitoneal injection of EB, and the effects on specific P450-dependent activities, immunoreactive P450 isozyme levels, and RNA levels were measured at various times after injection. Toluene was used as the test alkylbenzene for examination of the EB-mediated changes on in vitro hydrocarbon metabolism. In untreated rats, toluene was metabolized almost entirely by aliphatic hydroxylation (to benzyl alcohol); however, in EB-treated rats, significant quantities of benzyl alcohol, o-cresol, and p-cresol were produced. Interestingly, 5-10 h after EB treatment, there was a 40% decrease in benzyl alcohol production. By 24 h, rates of benzyl alcohol formation returned to control levels, whereas there was a 7-fold increase in o-cresol and a greater that 50-fold increase in p-cresol production. The changes in the disposition of toluene were then correlated with changes in particular P450 isozymes. Several P450 isozymes were induced after EB administration. P450 2B1/2-dependent testosterone 16 beta-hydroxylation and P450 2B1/2-immunoreactive protein were elevated 30-fold after EB administration, reaching maxima by 24 h and remaining elevated 48 h after exposure. Changes in P450 2B1 and 2B2 RNA preceded those of the proteins. Similar results were observed with P450 1A1. P450 2E1 RNA levels were elevated after a single EB injection. However, the elevation in P450 2E1-dependent activities and immunoreactive protein levels preceded the changes in RNA, suggesting that multiple steps are affected by EB exposure. In contrast to the increases in some isozymes, P450 2C11 protein was rapidly suppressed (within the first 2-10 h) after hydrocarbon exposure

  6. Cytochrome P450 2E1 gene polymorphisms/haplotypes and anti-tuberculosis drug-induced hepatitis in a Chinese cohort.

    Shaowen Tang

    Full Text Available The pathogenic mechanism of anti-tuberculosis (anti-TB drug-induced hepatitis is associated with drug metabolizing enzymes. No tagging single-nucleotide polymorphisms (tSNPs of cytochrome P450 2E1(CYP2E1 in the risk of anti-TB drug-induced hepatitis have been reported. The present study was aimed at exploring the role of tSNPs in CYP2E1 gene in a population-based anti-TB treatment cohort.A nested case-control study was designed. Each hepatitis case was 14 matched with controls by age, gender, treatment history, disease severity and drug dosage. The tSNPs were selected by using Haploview 4.2 based on the HapMap database of Han Chinese in Beijing, and detected by using TaqMan allelic discrimination technology.Eighty-nine anti-TB drug-induced hepatitis cases and 356 controls were included in this study. 6 tSNPs (rs2031920, rs2070672, rs915908, rs8192775, rs2515641, rs2515644 were genotyped and minor allele frequencies of these tSNPs were 21.9%, 23.0%, 19.1%, 23.6%, 20.8% and 44.4% in the cases and 20.9%, 22.7%, 18.9%, 23.2%, 18.2% and 43.2% in the controls, respectively. No significant difference was observed in genotypes or allele frequencies of the 6 tSNPs between case group and control group, and neither of haplotypes in block 1 nor in block 2 was significantly associated with the development of hepatitis.Based on the Chinese anti-TB treatment cohort, we did not find a statistically significant association between genetic polymorphisms of CYP2E1 and the risk of anti-TB drug-induced hepatitis. None of the haplotypes showed a significant association with the development of hepatitis in Chinese TB population.

  7. The 14CO2 breath test: Facilities and limitations of a rapid and noninvasive method for in vivo evaluation of modified hepatic cytochrome P-450 - a critique

    Bruech, M.; Kling, L.; Legrum, W.; Maser, E.

    1986-01-01

    By means of the breath test technique the cascade from O-demethylations to CO 2 was investigated after pretreatment of mice with warfarin, phenobarbital, cobaltous chloride, sodium vanadate and metyrapone. It was the intention to examine the validity of the technique with respect to cytochrome P-450 activity. Therefore three different radioactive labeled substrates, i.e., hydrogen carbonate, formate and xenobiotics, were applied at three different levels of the one-carbon pathway and were utilized to demonstrate possible interference of the modifiers with the sequence from O-demethylation to CO 2 . Real in vivo information about a modified cytochrome P-450 system can be obtained using model substrates carefully selected with regard to the type of expected modification of the monooxygenase system. In addition, a parallel monitoring of the consecutive reaction sequence by measuring the conversion of formate to CO 2 is necessary in order to guarantee the validity of the in vivo technique in visualizing the activity of the hepatic monooxygenase system. (orig.)

  8. Effects of tin-protoporphyrin administration on hepatic xenobiotic metabolizing enzymes in the juvenile rat

    Stout, D.L.; Becker, F.F.

    1988-01-01

    The heme analogue tin-protoporphyrin IX (SnP) is a potent inhibitor of microsomal heme oxygenase. Administration of SnP to neonatal rats can prevent hyperbilirubinemia by blocking the postnatal increase of heme oxygenase activity. Apparently innocuous at therapeutic doses, it is of potential clinical value for chemoprevention of neonatal jaundice. We found that when 50-g male Sprague-Dawley rats were treated daily with 50 mumol of SnP/kg sc for 6 days, hepatic microsomal cytochromes b5 and P-450 were significantly diminished. Cytochrome P-450 reductase, two P-450-dependent monooxygenases, aminopyrine demethylase and benzo(a)pyrene hydroxylase, and catalase, a peroxisomal hemoprotein, were also significantly diminished. These results suggested that SnP might significantly affect the metabolism of other xenobiotics. This possibility was confirmed by the finding that hexobarbital-induced sleep lasted 4 times longer in SnP-treated rats than in controls. Inhibition of protein synthesis by SnP was ruled out as the cause of hemoprotein loss when administration of [ 3 H]leucine to SnP-treated and control rats demonstrated that proteins of the microsomal, cytosolic, and plasma membrane fractions of the livers from both groups incorporated similar levels of leucine. When 55 FeCl 3 and [2- 14 C]glycine were administered to measure heme synthesis, heme extract from the livers of SnP-treated rats contained 4 times more label from iron and glycine than did heme from control livers. Despite the apparent increased rate of heme synthesis in SnP-treated rats, each of the three cell fractions demonstrated a significant loss of heme but contained sizable amounts of SnP. These findings suggest that SnP causes a decrease of functional hemoprotein and partial loss of enzymic activity by displacing intracellular heme

  9. Hepatic Metabolism of Sakuranetin and Its Modulating Effects on Cytochrome P450s and UDP-Glucuronosyltransferases

    Hyesoo Jeong

    2018-06-01

    Full Text Available Sakuranetin (SKN, found in cherry trees and rice, is a flavanone with various pharmacological activities. It is biosynthesized from naringenin in rice or cherry trees, and the metabolism of SKN has been studied in non-human species. The present study aimed to investigate the metabolic pathways of SKN in human liver microsomes and identify the phase I and phase II metabolites, as well as evaluate the potential for drug–herb interactions through the modulation of drug metabolizing enzymes (DMEs. HPLC-DAD and HPLC-electrospray mass spectrometry were used to study the metabolic stability and identify the metabolites from human liver microsomes incubated with SKN. The potential of SKN to inhibit the DMEs was evaluated by monitoring the formation of a DME-specific product. The cytochrome P450 2B6 and 3A4-inductive effects were studied using promoter reporter assays in human hepatocarcinoma cells. The major pathways for SKN metabolism include B-ring hydroxylation, 5-O-demethylation, and conjugation with glutathione or glucuronic acid. The phase I metabolites were identified as naringenin and eriodictyol. SKN was found to be a UDP-glucuronosyltransferases (UGT 1A9 inhibitor, whereas it induced transactivation of the human pregnane X receptor-mediated cytochrome P450 (CYP 3A4 gene.

  10. Hepatitis

    ... most common types of viral hepatitis. What Is Hepatitis A? For kids, hep A is the most common ... they recover, it does not come back. Can Hepatitis A Be Prevented? The following will help keep people ...

  11. Major antigen of liver kidney microsomal autoantibodies in idiopathic autoimmune hepatitis is cytochrome P450db1.

    Manns, M P; Johnson, E F; Griffin, K J; Tan, E M; Sullivan, K F

    1989-01-01

    Type 1, liver kidney microsomal autoantibodies (LKM-1) are associated with a subgroup of idiopathic autoimmune type, chronic active hepatitis (CAH). The antigenic specificity of LKM-1 autoantibodies from 13 patients was investigated by immunoblot analysis of human liver microsomal proteins. Polypeptides of 50, 55, and 64 kD were detected with these antisera. A high titer LKM-1 serum was selected to screen a human liver lambda gt11 cDNA expression library, resulting in the isolation of several...

  12. Ascorbic acid deficiency decreases hepatic cytochrome P-450, especially CYP2B1/2B2, and simultaneously induces heme oxygenase-1 gene expression in scurvy-prone ODS rats.

    Kobayashi, Misato; Hoshinaga, Yukiko; Miura, Natsuko; Tokuda, Yuki; Shigeoka, Shigeru; Murai, Atsushi; Horio, Fumihiko

    2014-01-01

    The mechanisms underlying the decrease in hepatic cytochrome P-450 (CYP) content in ascorbic acid deficiency was investigated in scurvy-prone ODS rats. First, male ODS rats were fed a diet containing sufficient ascorbic acid (control) or a diet without ascorbic acid (deficient) for 18 days, with or without the intraperitoneal injection of phenobarbital. Ascorbic acid deficiency decreased hepatic microsomal total CYP content, CYP2B1/2B2 protein, and mitochondrial cytochrome oxidase (COX) complex IV subunit I protein, and simultaneously increased heme oxygenase-1 protein in microsomes and mitochondria. Next, heme oxygenase-1 inducers, that is lipopolysaccharide and hemin, were administered to phenobaribital-treated ODS rats fed sufficient ascorbic acid. The administration of these inducers decreased hepatic microsomal total CYP content, CYP2B1/2B2 protein, and mitochondrial COX complex IV subunit I protein. These results suggested that the stimulation of hepatic heme oxygenase-1 expression by ascorbic acid deficiency caused the decrease in CYP content in liver.

  13. Ethanol metabolism by alcohol dehydrogenase or cytochrome P450 2E1 differentially impairs hepatic protein trafficking and growth hormone signaling.

    Doody, Erin E; Groebner, Jennifer L; Walker, Jetta R; Frizol, Brittnee M; Tuma, Dean J; Fernandez, David J; Tuma, Pamela L

    2017-12-01

    The liver metabolizes alcohol using alcohol dehydrogenase (ADH) and cytochrome P 450 2E1 (CYP2E1). Both enzymes metabolize ethanol into acetaldehyde, but CYP2E1 activity also results in the production of reactive oxygen species (ROS) that promote oxidative stress. We have previously shown that microtubules are hyperacetylated in ethanol-treated polarized, hepatic WIF-B cells and livers from ethanol-fed rats. We have also shown that enhanced protein acetylation correlates with impaired clathrin-mediated endocytosis, constitutive secretion, and nuclear translocation and that the defects are likely mediated by acetaldehyde. However, the roles of CYP2E1-generated metabolites and ROS in microtubule acetylation and these alcohol-induced impairments have not been examined. To determine if CYP2E1-mediated alcohol metabolism is required for enhanced acetylation and the trafficking defects, we coincubated cells with ethanol and diallyl sulfide (DAS; a CYP2E1 inhibitor) or N -acetyl cysteine (NAC; an antioxidant). Both agents failed to prevent microtubule hyperacetylation in ethanol-treated cells and also failed to prevent impaired secretion or clathrin-mediated endocytosis. Somewhat surprisingly, both DAS and NAC prevented impaired STAT5B nuclear translocation. Further examination of microtubule-independent steps of the pathway revealed that Jak2/STAT5B activation by growth hormone was prevented by DAS and NAC. These results were confirmed in ethanol-exposed HepG2 cells expressing only ADH or CYP2E1. Using quantitative RT-PCR, we further determined that ethanol exposure led to blunted growth hormone-mediated gene expression. In conclusion, we determined that alcohol-induced microtubule acetylation and associated defects in microtubule-dependent trafficking are mediated by ADH metabolism whereas impaired microtubule-independent Jak2/STAT5B activation is mediated by CYP2E1 activity. NEW & NOTEWORTHY Impaired growth hormone-mediated signaling is observed in ethanol

  14. Establishment of a novel radioligand assay using eukaryotically expressed cytochrome P4502D6 for the measurement of liver kidney microsomal type 1 antibody in patients with autoimmune hepatitis and hepatitis C virus infection.

    Ma, Y; Gregorio, G; Gäken, J; Muratori, L; Bianchi, F B; Mieli-Vergani, G; Vergani, D

    1997-06-01

    Liver kidney microsomal type 1 antibody (LKM1) is the diagnostic marker of autoimmune hepatitis (AIH) type 2 and is also found in patients with hepatitis C virus (HCV) infection. Cytochrome P4502D6 (CYP2D6) is the documented target antigen of LKM1 in AIH, but not in HCV infection. To compare the reactivity in the two conditions, we established a radioligand assay using eukaryotically expressed CYP2D6 as target. A 1.2-kb human CYP2D6 cDNA was isolated from a human liver cDNA library and subcloned into an in vitro transcription vector pSP64 Poly(A). Recombinant CYP2D6 was then produced by in vitro transcription/translation, metabolically labelled with 35S methionine and used in the immunoprecipitation assay. Antibodies that bound radiolabelled CYP2D6 were immunoprecipitated and their levels assessed as cpm. Sera from 50 LKM1-positive patients (26 with AIH; 24 with HCV infection), 128 LKM1-negative patients and 57 normal controls were tested. Reactivity to 35S labelled CYP2D6 was observed in all LKM1-positive sera from patients with AIH and HCV infection, but in none of the controls. The cpm in both conditions were significantly higher than in normal controls (pLKM1 (r 0.87, p<0.001 and r=0.64, p<0.001 for AIH and HCV infection, respectively). Reactivity to 35S labelled CYP2D6 was inhibited by addition of an excess of eukaryotically expressed CYP2D6. CYP2D6 is a major target antigen of both AIH and HCV infection. The novel radioligand assay is highly sensitive and specific.

  15. Short-term hepatic effects of depleted uranium on xenobiotic and bile acid metabolizing cytochrome P450 enzymes in the rat

    Gueguen, Y.; Souidi, M.; Baudelin, C.; Dudoignon, N.; Grison, S.; Dublineau, I.; Marquette, C.; Voisin, P.; Gourmelon, P.; Aigueperse, J.

    2006-01-01

    The toxicity of uranium has been demonstrated in different organs, including the kidneys, skeleton, central nervous system, and liver. However, few works have investigated the biological effects of uranium contamination on important metabolic function in the liver. In vivo studies were conducted to evaluate its effects on cytochrome P450 (CYP) enzymes involved in the metabolism of cholesterol and xenobiotics in the rat liver. The effects of depleted uranium (DU) contamination on Sprague-Dawley were measured at 1 and 3 days after exposure. Biochemical indicators characterizing liver and kidney functions were measured in the plasma. The DU affected bile acid CYP activity: 7α-hydroxycholesterol plasma level decreased by 52% at day 3 whereas microsomal CYP7A1 activity in the liver did not change significantly and mitochondrial CYP27A1 activity quintupled at day 1. Gene expression of the nuclear receptors related to lipid metabolism (FXR and LXR) also changed, while PPARα mRNA levels did not. The increased mRNA levels of the xenobiotic-metabolizing CYP3A enzyme at day 3 may be caused by feedback up-regulation due to the decreased CYP3A activity at day 1. CAR mRNA levels, which tripled on day 1, may be involved in this up-regulation, while mRNA levels of PXR did not change. These results indicate that high levels of depleted uranium, acting through modulation of the CYP enzymes and some of their nuclear receptors, affect the hepatic metabolism of bile acids and xenobiotics. (orig.)

  16. Prevention of LDL-suppression of HMG-CoA reductase (HMGR) activity by progesterone (PG): evidence for cytochrome P-450 involvement

    Sexton, R.C.; Gupta, A.; Panini, S.R.; Rudney, H.

    1987-01-01

    Incubation of rat intestinal epithelial cells (IEC-6) with PG has been reported by us to prevent the suppression of HMGR activity by LDL. In the present study, addition of LDL and PG to IEC-6 cells resulted in a 2 fold increase in cellular free cholesterol (CH) in 24 h, while HMGR activity remained elevated. PG did not affect the internalization and degradation of [ 125 I] LDL nor the accumulation of free [ 3 H] CH in cells incubated with [ 3 H-cholesteryl linoleate]-LDL. Also, PG did not affect the intracellular transport of LDL-derived [ 3 H] CH to the plasma membrane nor the efflux of the [ 3 H] CH into medium containing human high density lipoprotein. Addition of LDL to cells, in which the cellular CH was radiolabeled from [ 3 H] acetate, resulted in an increased formation of radiolabeled oxysterols, detected by HPLC, and a corresponding decrease in HMGR activity. PG attenuated both the LDL-induced formation of oxysterols and suppression of HMGR activity. PG inhibited cytochrome P-450 dependent oxidation of benzphetamine, aminopyrine and aniline by liver microsomes from phenobarbitol treated rats. These results suggest PG may prevent LDL suppression of HMGR activity in IEC-6 cells by inhibiting cytochrome P-450 dependent formation of regulatory oxysterols

  17. Stereo-selectivity and regio-selectivity in the metabolism of 7,8-dihydrobenzo[a]pyrene by cytochrome P450, epoxide hydrolase and hepatic microsomes from 3-methylcholanthrene-treated rats.

    Adams, J D; Yagi, H; Levin, W; Jerina, D M

    1995-03-30

    The active site of cytochrome P450 1A1 has been probed with the substrate 7,8-dihydrobenzo[a]pyrene using a purified, reconstituted system composed of cytochrome P450 1A1, NADPH-cytochrome c reductase and lipid in the presence or absence of epoxide hydrolase. The turnover of the substrate was found to be 38 nmol/nmol of cytochrome P450/min. The metabolic products that were identified are: a phenolic 7,8-dihydrobenzo[a]pyrene (20-29%); 9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (17-28%); benzo[a]pyrene (12-19%); 7-hydroxy-7,8-dihydrobenzo[a]pyrene (13-16%); 8-hydroxy-7,8-dihydrobenzo[a]pyrene (7-15%); 3-hydroxybenzo[a]pyrene (7-15%); 4,5-epoxy-4,5,7,8-tetrahydrobenzo[a]pyrene (0-4%); and a triol of 7,8,9,10-tetrahydrobenzo[a]pyrene (0-4%). 9,10-Epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene undergoes rapid hydrolysis to cis- and trans-9,10-dihydroxy-dihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (2:1) by benzylic attack of water at C-10. Approximately 71% of the trans diols are derived from (+)-(9S,10R)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, indicating that cytochrome P450 1A1 has more than a 2:1 preference for selective epoxidation of an enantiotopic face of 7,8-dihydrobenzo[a]pyrene. This stereo-selectivity agrees with the postulated stereo-selectivity predicted by a previously described active site model for cytochrome P450 1A1. Epoxide hydrolase in pure form or in hepatic microsomes catalyzes the hydrolysis of 9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, which is inhibited by 1,1,1-trichloropropane 2,3-oxide. The (+)-(9S,10R)-isomer of the epoxide is slightly preferred as a substrate over its enantiomer and is cleaved by benzylic and nonbenzylic attack. Only benzylic attack was found with (-)-(9R,10S)-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.

  18. Interactions of pharmaceuticals and other xenobiotics on hepatic pregnane X receptor and cytochrome P450 3A signaling pathway in rainbow trout (Oncorhynchus mykiss)

    Wassmur, Britt; Graens, Johanna; Kling, Peter; Celander, Malin C.

    2010-01-01

    The pregnane X receptor (PXR) belongs to the nuclear hormone receptor (NR) superfamily and is commonly described as a xenophore or a pharmacophore, as it can be activated by a wide array of xenobiotics, including numerous pharmaceuticals and other environmental pollutants. The PXR regulates expression of e.g. cytochrome P450 3A (CYP3A) and the P-glycoprotein (P-gp) that are involved in excretion of lipophilic xenobiotics and endobiotics. A full length PXR cDNA was isolated from rainbow trout liver and it was expressed in a descending order of magnitude in liver > intestine > kidney > heart. A rainbow trout PXR reporter assay was developed and a suite of pharmaceuticals and other xenobiotics were screened. However, no specific activation of rainbow trout PXR was observed with the substances tested. Interactions of prototypical PXR agonists on PXR signaling in rainbow trout were further investigated in cells of hepatic origin exposed in vitro and in juvenile rainbow trout exposed in vivo. The rainbow trout hepatoma cell line (RTH-149), displayed 600 times lower expression of CYP3A mRNA compared to primary cultures of hepatocytes, and did not respond to treatment with either pregnenolone 16α-carbonitrile (PCN), ketoconazole (KCZ) or rifampicin (RIF), which implies a non-functional PXR in this cell line. Exposure of hepatocytes to PCN and lithocholic acid (LA), resulted in a weak concentration-dependent induction of CYP3A and P-gp mRNA levels, though, exposure to the higher concentration of LA (50 μM) decreased PXR mRNA levels. Exposure to dexamethasone (DEX) resulted in a decrease in PXR mRNA, without affecting CYP3A mRNA levels in hepatocytes in vitro. Injections of rainbow trout in vivo with 1 mg LA/kg fish resulted in a slight (albeit not significant) increase in CYP3A mRNA levels without affecting PXR mRNA levels. Although, injection with 10 mg omeprazole (OME)/kg fish had no effect on PXR and CYP3A mRNA levels, a 60% inhibition of CYP3A enzyme activities was

  19. Interactions of pharmaceuticals and other xenobiotics on hepatic pregnane X receptor and cytochrome P450 3A signaling pathway in rainbow trout (Oncorhynchus mykiss)

    Wassmur, Britt; Graens, Johanna; Kling, Peter [University of Gothenburg, Department of Zoology, Box 463, SE-405 30 Goeteborg (Sweden); Celander, Malin C., E-mail: malin.celander@zool.gu.se [University of Gothenburg, Department of Zoology, Box 463, SE-405 30 Goeteborg (Sweden)

    2010-10-01

    The pregnane X receptor (PXR) belongs to the nuclear hormone receptor (NR) superfamily and is commonly described as a xenophore or a pharmacophore, as it can be activated by a wide array of xenobiotics, including numerous pharmaceuticals and other environmental pollutants. The PXR regulates expression of e.g. cytochrome P450 3A (CYP3A) and the P-glycoprotein (P-gp) that are involved in excretion of lipophilic xenobiotics and endobiotics. A full length PXR cDNA was isolated from rainbow trout liver and it was expressed in a descending order of magnitude in liver > intestine > kidney > heart. A rainbow trout PXR reporter assay was developed and a suite of pharmaceuticals and other xenobiotics were screened. However, no specific activation of rainbow trout PXR was observed with the substances tested. Interactions of prototypical PXR agonists on PXR signaling in rainbow trout were further investigated in cells of hepatic origin exposed in vitro and in juvenile rainbow trout exposed in vivo. The rainbow trout hepatoma cell line (RTH-149), displayed 600 times lower expression of CYP3A mRNA compared to primary cultures of hepatocytes, and did not respond to treatment with either pregnenolone 16{alpha}-carbonitrile (PCN), ketoconazole (KCZ) or rifampicin (RIF), which implies a non-functional PXR in this cell line. Exposure of hepatocytes to PCN and lithocholic acid (LA), resulted in a weak concentration-dependent induction of CYP3A and P-gp mRNA levels, though, exposure to the higher concentration of LA (50 {mu}M) decreased PXR mRNA levels. Exposure to dexamethasone (DEX) resulted in a decrease in PXR mRNA, without affecting CYP3A mRNA levels in hepatocytes in vitro. Injections of rainbow trout in vivo with 1 mg LA/kg fish resulted in a slight (albeit not significant) increase in CYP3A mRNA levels without affecting PXR mRNA levels. Although, injection with 10 mg omeprazole (OME)/kg fish had no effect on PXR and CYP3A mRNA levels, a 60% inhibition of CYP3A enzyme activities

  20. In vitro complex formation and inhibition of hepatic cytochrome P450 activity by different macrolides and tiamulin in goats and cattle

    Zweers-Zeilmaker, W.M.; Miert, A.S.J.P.A.M. van; Horbach, G.J.; Witkamp, R.F.

    1998-01-01

    In humans, clinically relevant drug–drug interactions occur with some macrolide antibiotics via the formation of stable metabolic intermediate (MI) complexes with enzymes of the cytochrome P4503A (CYP3A) subfamily. The formation of such complexes can result in a decreased biotransformation rate of

  1. /sup 14/CO/sub 2/ breath test: Facilities and limitations of a rapid and noninvasive method for in vivo evaluation of modified hepatic cytochrome P-450 - a critique

    Bruech, M.; Kling, L.; Legrum, W.; Maser, E.

    1986-05-01

    By means of the breath test technique the cascade from O-demethylations to CO/sub 2/ was investigated after pretreatment of mice with warfarin, phenobarbital, cobaltous chloride, sodium vanadate and metyrapone. It was the intention to examine the validity of the technique with respect to cytochrome P-450 activity. Therefore three different radioactive labeled substrates, i.e., hydrogen carbonate, formate and xenobiotics, were applied at three different levels of the one-carbon pathway and were utilized to demonstrate possible interference of the modifiers with the sequence from O-demethylation to CO/sub 2/. Real in vivo information about a modified cytochrome P-450 system can be obtained using model substrates carefully selected with regard to the type of expected modification of the monooxygenase system. In addition, a parallel monitoring of the consecutive reaction sequence by measuring the conversion of formate to CO/sub 2/ is necessary in order to guarantee the validity of the in vivo technique in visualizing the activity of the hepatic monooxygenase system.

  2. Differences in hepatic microsomal cytochrome P-450 isoenzyme induction by pyrazole, chronic ethanol, 3-methylcholanthrene, and phenobarbital in high alcohol sensitivity (HAS) and low alcohol sensitivity (LAS) rats.

    Lucas, D; Ménez, J F; Berthou, F; Cauvin, J M; Deitrich, R A

    1992-10-01

    High and low alcohol sensitivity (HAS and LAS) rats have been selected for their differences in ethanol-induced sleep time. Liver monooxygenase activities were studied in HAS and LAS rats before and after treatments with known inducers such as chronic ethanol, pyrazole, 3-methylcholanthrene (3-MC) and phenobarbital (PB) to determine whether the selection procedure also selected for differences in the cytochrome P-450 (P-450) inducibility. This previously has been shown with long sleep (LS) and short sleep (SS) mice, which were selected using a similar criterion. 3-MC and PB, in conjunction with chronic ethanol treatment, were used in order to evaluate the interactions of ethanol with these inducers. Prior to treatment, total P-450 content was slightly lower in LAS than in HAS rats. However, both lines displayed the same microsomal monooxygenase activities related to different P-450 isozymes. This was demonstrated by ethoxyresorufin deethylation (EROD) for cytochrome P-450 1A1 (CYP1A1), acetanilide hydroxylation (ACET) for CYP1A2, pentoxyresorufin dealkylation (PROD) for CYP2B, 1-butanol oxidation (BUTAN) and N-nitrosodimethylamine demethylation (NDMA) for CYP2E1. After the different treatments, HAS rats did not differ from LAS rats in their CYP2E1 inducibility. However, pyrazole, PB and 3-MC treatment led to differences in CYP1A and CYP2B monooxygenase activities between the two lines. The enhancement of PROD by pyrazole treatment was less prominent in LAS (1.7-fold of the control value) than in HAS rats (3.8-fold).(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Influence of some anti-inflammatory drugs on the activity of aryl hydrocarbon hydroxylase and the cytochrome P450 content

    Mostafa, M.H.; Sheweita, S.A.; Abdel-Moneam, N.M. (Alexandria Univ. (Egypt))

    1990-06-01

    The metabolism of benzo({alpha})pyrene is mediated by the mixed function oxidase system including the cytochrome P450-dependent aryl hydrocarbon hydroxylase. The data of the present study revealed the ability of various commonly used anti-inflammatory drugs to alter the activity of this enzyme system, where all the tested drugs, namely phenyl butazone, ketoprofen, piroxicam, and acetaminophen, caused an increase in both the activity of aryl hydrocarbon hydroxylase and the cytochrome P450 content whether administered as a single dose or as a repeated dose for 6 consecutive days. The percentage of change for all drugs except phenyl butazone was proportional to the duration of drug administration. On the other hand, pyrazole which is chemically related to phenyl butazone, had no significant effect when administered as a single dose but caused a decrease in both studied parameters when administered as a repeated dose for 6 consecutive days. The mechanisms by which these commonly used drugs modify the aryl hydrocarbon hydroxylase activity and the cytochrome p450 content are discussed in the text.

  4. In vitro complex formation and inhibition of hepatic cytochrome P450 activity by different macrolides and tiamulin in goats and cattle.

    Zweers-Zeilmaker, W M; Van Miert, A S; Horbach, G J; Witkamp, R F

    1999-02-01

    In humans, clinically relevant drug-drug interactions occur with some macrolide antibiotics via the formation of stable metabolic intermediate (MI) complexes with enzymes of the cytochrome P4503A (CYP3A) subfamily. The formation of such complexes can result in a decreased biotransformation rate of simultaneously administered drugs. In previous studies it was shown that the veterinary antibiotic tiamulin was also able to form a stable MI complex in pigs and rats. In the present study the relative CYP3A inhibiting potency and MI complex formation of a series of macrolide antibiotics and tiamulin were studied in microsomal fractions of goat and cattle and in a cell-line expressing bovine CYP3A. Tiamulin and triacetyloleandomycin (TAO) were found to be effective inhibitors of CYP450 activity in all systems tested. Erythromycin and tilmicosin were found to be relatively less effective inhibitors of CYP450 activity in microsomes, and their activity in the bovine CYP3A4 expressing cell line was relatively weak. Tylosin was shown to be a weak inhibitor in microsomes and not in the cell line, whereas spiramycin had no effect at all. MI-complex formation measured by spectral analysis was seen with TAO, tiamulin, erythromycin and tylosin, but not with tilmicosin and spiramycin. Although additional factors play a role in vivo, these results may explain potential drug-drug interactions and differences between related compounds in this respect.

  5. Strategies for Determining Correct Cytochrome P450 Contributions in Hepatic Clearance Predictions: In Vitro-In Vivo Extrapolation as Modelling Approach and Tramadol as Proof-of Concept Compound.

    T'jollyn, Huybrecht; Snoeys, Jan; Van Bocxlaer, Jan; De Bock, Lies; Annaert, Pieter; Van Peer, Achiel; Allegaert, Karel; Mannens, Geert; Vermeulen, An; Boussery, Koen

    2017-06-01

    Although the measurement of cytochrome P450 (CYP) contributions in metabolism assays is straightforward, determination of actual in vivo contributions might be challenging. How representative are in vitro for in vivo CYP contributions? This article proposes an improved strategy for the determination of in vivo CYP enzyme-specific metabolic contributions, based on in vitro data, using an in vitro-in vivo extrapolation (IVIVE) approach. Approaches are exemplified using tramadol as model compound, and CYP2D6 and CYP3A4 as involved enzymes. Metabolism data for tramadol and for the probe substrates midazolam (CYP3A4) and dextromethorphan (CYP2D6) were gathered in human liver microsomes (HLM) and recombinant human enzyme systems (rhCYP). From these probe substrates, an activity-adjustment factor (AAF) was calculated per CYP enzyme, for the determination of correct hepatic clearance contributions. As a reference, tramadol CYP contributions were scaled-back from in vivo data (retrograde approach) and were compared with the ones derived in vitro. In this view, the AAF is an enzyme-specific factor, calculated from reference probe activity measurements in vitro and in vivo, that allows appropriate scaling of a test drug's in vitro activity to the 'healthy volunteer' population level. Calculation of an AAF, thus accounts for any 'experimental' or 'batch-specific' activity difference between in vitro HLM and in vivo derived activity. In this specific HLM batch, for CYP3A4 and CYP2D6, an AAF of 0.91 and 1.97 was calculated, respectively. This implies that, in this batch, the in vitro CYP3A4 activity is 1.10-fold higher and the CYP2D6 activity 1.97-fold lower, compared to in vivo derived CYP activities. This study shows that, in cases where the HLM pool does not represent the typical mean population CYP activities, AAF correction of in vitro metabolism data, optimizes CYP contributions in the prediction of hepatic clearance. Therefore, in vitro parameters for any test compound

  6. Impact of Fusarium mycotoxins on hepatic and intestinal mRNA expression of cytochrome P450 enzymes and drug transporters, and on the pharmacokinetics of oral enrofloxacin in broiler chickens.

    Antonissen, Gunther; Devreese, Mathias; De Baere, Siegrid; Martel, An; Van Immerseel, Filip; Croubels, Siska

    2017-03-01

    Cytochrome P450 (CYP450) drug biotransformation enzymes and multidrug resistance (MDR) proteins may influence drug disposition processes. The first part of the study aimed to evaluate the effect of mycotoxins deoxynivalenol (DON) and/or fumonisins (FBs), at contamination levels approaching European Union guidance levels, on intestinal and hepatic CYP450 enzymes and MDR proteins gene expression in broiler chickens. mRNA expression of genes encoding CYP450 enzymes (CYP3A37, CYP1A4 and CYP1A5) and drug transporters (MDR1/ABCB1 and MRP2/ABCC2) was determined using qRT-PCR. A significant up-regulation of CYP1A4 (P = 0.037) and MDR1 (P = 0.036) was observed in the jejunum of chickens fed a diet contaminated with FBs. The second part of this study aimed to investigate the impact of feeding a FBs contaminated diet on the oral absorption of enrofloxacin (10 mg/kg BW), a MDR1 substrate. A significant (P = 0.045), however small, decreased area under the plasma concentration-time curve (AUC 0-48  h, mean ± SD) was observed for enrofloxacin in chickens fed the FBs contaminated diet compared to the control group, 16.28 ± 1.82 h μg/mL versus 18.27 ± 1.79 h μg/mL. These findings suggest that concurrent administration of drugs with FBs contaminated feed might alter the pharmacokinetic characteristics of CYP1A4 substrate drugs and MDR1 substrates, such as enrofloxacin. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Over-expression of a cytochrome P450 is associated with resistance to pyriproxyfen in the greenhouse whitefly Trialeurodes vaporariorum.

    Nikos Karatolos

    Full Text Available The juvenile hormone mimic, pyriproxyfen is a suppressor of insect embryogenesis and development, and is effective at controlling pests such as the greenhouse whitefly Trialeurodes vaporariorum (Westwood which are resistant to other chemical classes of insecticides. Although there are reports of insects evolving resistance to pyriproxyfen, the underlying resistance mechanism(s are poorly understood.Bioassays against eggs of a German (TV8 population of T. vaporariorum revealed a moderate level (21-fold of resistance to pyriproxyfen. This is the first time that pyriproxyfen resistance has been confirmed in this species. Sequential selection of TV8 rapidly generated a strain (TV8pyrsel displaying a much higher resistance ratio (>4000-fold. The enzyme inhibitor piperonyl butoxide (PBO suppressed this increased resistance, indicating that it was primarily mediated via metabolic detoxification. Microarray analysis identified a number of significantly over-expressed genes in TV8pyrsel as candidates for a role in resistance including cytochrome-P450 dependent monooxygenases (P450s. Quantitative PCR highlighted a single P450 gene (CYP4G61 that was highly over-expressed (81.7-fold in TV8pyrsel.Over-expression of a single cytochrome P450 gene (CYP4G61 has emerged as a strong candidate for causing the enhanced resistance phenotype. Further work is needed to confirm the role of the encoded P450 enzyme CYP4G61 in detoxifying pyriproxyfen.

  8. One-electron reduction of mitomycin c by rat liver : role of cytochrome P-450 and NADPH-cytochrome P-450 reductase

    Vromans, R M; Van de Straat, R; Groeneveld, M.; Vermeulen, N P

    1. The role of cytochrome P-450 in the one-electron reduction of mitomycin c was studied in rat hepatic microsomal systems and in reconstituted systems of purified cytochrome P-450. Formation of H2O2 from redox cycling of the reduced mitomycin c in the presence of O2 and the alkylation of

  9. Hepatic Encephalopathy

    Full Text Available ... Disease Type 1 (von Gierke) Hemochromatosis Hepatic Encephalopathy Hepatitis A Hepatitis B Hepatitis C Intrahepatic Cholestasis of Pregnancy ( ... Disease Type 1 (von Gierke) Hemochromatosis Hepatic Encephalopathy Hepatitis A Hepatitis B Hepatitis C Intrahepatic Cholestasis of Pregnancy ( ...

  10. Hepatitis C

    ... Workshops Follow Us Home Health Information Liver Disease Hepatitis (Viral) Hepatitis C Related Topics English English Español Section Navigation Hepatitis (Viral) What Is Viral Hepatitis? Hepatitis A Hepatitis B ...

  11. A complex of cardiac cytochrome c1 and cytochrome c.

    Chiang, Y L; Kaminsky, L S; King, T E

    1976-01-10

    The interactions of cytochrome c1 and cytochrome c from bovine cardiac mitochondria were investigated. Cytochrome c1 and cytochrome c formed a 1:1 molecular complex in aqueous solutions of low ionic strength. The complex was stable to Sephadex G-75 chromatography. The formation and stability of the complex were independent of the oxidation state of the cytochrome components as far as those reactions studied were concerned. The complex was dissociated in solutions of ionic strength higher than 0.07 or pH exceeding 10 and only partially dissociated in 8 M urea. No complexation occurred when cytochrome c was acetylated on 64% of its lysine residues or photooxidized on its 2 methionine residues. Complexes with molecular ratios of less than 1:1 (i.e. more cytochrome c) were obtained when polymerized cytochrome c, or cytochrome c with all lysine residues guanidinated, or a "1-65 heme peptide" from cyanogen bromide cleavage of cytochrome c was used. These results were interpreted to imply that the complex was predominantly maintained by ionic interactions probably involving some of the lysine residues of cytochrome c but with major stabilization dependent on the native conformations of both cytochromes. The reduced complex was autooxidizable with biphasic kinetics with first order rate constants of 6 X 10(-5) and 5 X U0(-5) s-1 but did not react with carbon monoxide. The complex reacted with cyanide and was reduced by ascorbate at about 32% and 40% respectively, of the rates of reaction with cytochrome c alone. The complex was less photoreducible than cytochrome c1 alone. The complex exhibited remarkably different circular dichroic behavior from that of the summation of cytochrome c1 plus cytochrome c. We concluded that when cytochromes c1 and c interacted they underwent dramatic conformational changes resulting in weakening of their heme crevices. All results available would indicate that in the complex cytochrome c1 was bound at the entrance to the heme crevice of

  12. Hepatic Encephalopathy

    Full Text Available ... Related Liver Disease Alpha-1 Antitrypsin Deficiency Autoimmune Hepatitis Benign Liver Tumors Biliary Atresia Cirrhosis of the ... Disease Type 1 (von Gierke) Hemochromatosis Hepatic Encephalopathy Hepatitis A Hepatitis B Hepatitis C Intrahepatic Cholestasis of ...

  13. Hepatic Encephalopathy

    Full Text Available ... Hemochromatosis Hepatic Encephalopathy Hepatitis A Hepatitis B Hepatitis C Intrahepatic Cholestasis of Pregnancy (ICP) Jaundice In Newborns ... are the common causes of cirrhosis? Hepatitis B & C Alcohol-related Liver Disease Non-alcoholic Fatty Liver ...

  14. Cytochrome oxidase assembly does not require catalytically active cytochrome C.

    Barrientos, Antoni; Pierre, Danielle; Lee, Johnson; Tzagoloff, Alexander

    2003-03-14

    Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the transfer of electrons from reduced cytochrome c to molecular oxygen. COX assembly requires the coming together of nuclear- and mitochondrial-encoded subunits and the assistance of a large number of nuclear gene products acting at different stages of maturation of the enzyme. In Saccharomyces cerevisiae, expression of cytochrome c, encoded by CYC1 and CYC7, is required not only for electron transfer but also for COX assembly through a still unknown mechanism. We have attempted to distinguish between a functional and structural requirement of cytochrome c in COX assembly. A cyc1/cyc7 double null mutant strain was transformed with the cyc1-166 mutant gene (Schweingruber, M. E., Stewart, J. W., and Sherman, F. (1979) J. Biol. Chem. 254, 4132-4143) that expresses stable but catalytically inactive iso-1-cytochrome c. The COX content of the cyc1/cyc7 double mutant strain harboring non-functional iso-1-cytochrome c has been characterized spectrally, functionally, and immunochemically. The results of these studies demonstrate that cytochrome c plays a structural rather than functional role in assembly of cytochrome c oxidase. In addition to its requirement for COX assembly, cytochrome c also affects turnover of the enzyme. Mutants containing wild type apocytochrome c in mitochondria lack COX, suggesting that only the folded and mature protein is able to promote COX assembly.

  15. The mechanism by which oxygen and cytochrome c increase the rate of electron transfer from cytochrome a to cytochrome a3 of cytochrome c oxidase.

    Bickar, D; Turrens, J F; Lehninger, A L

    1986-11-05

    When cytochrome c oxidase is isolated from mitochondria, the purified enzyme requires both cytochrome c and O2 to achieve its maximum rate of internal electron transfer from cytochrome a to cytochrome a3. When reductants other than cytochrome c are used, the rate of internal electron transfer is very slow. In this paper we offer an explanation for the slow reduction of cytochrome a3 when reductants other than cytochrome c are used and for the apparent allosteric effects of cytochrome c and O2. Our model is based on the conventional understanding of cytochrome oxidase mechanism (i.e. electron transfer from cytochrome a/CuA to cytochrome a3/CuB), but assumes a relatively rapid two-electron transfer between cytochrome a/CuA and cytochrome a3/CuB and a thermodynamic equilibrium in the "resting" enzyme (the enzyme as isolated) which favors reduced cytochrome a and oxidized cytochrome a3. Using the kinetic constants that are known for this reaction, we find that the activating effects of O2 and cytochrome c on the rate of electron transfer from cytochrome a to cytochrome a3 conform to the predictions of the model and so provide no evidence of any allosteric effects or control of cytochrome c oxidase by O2 or cytochrome c.

  16. Immunohistochemical detection of cytochrome P450 isoenzymes in cultured human epidermal cells.

    Van Pelt, F N; Meierink, Y J; Blaauboer, B J; Weterings, P J

    1990-12-01

    We used specific monoclonal antibodies (MAb) to human cytochrome P450 isoenzymes to determine the presence of these proteins in human epidermal cells. Two MAb (P450-5 and P450-8) recognize major forms of hepatic cytochrome P450 involved in biotransformation of xenobiotics. A third MAb, to cytochrome P450-9, is not fully characterized. The proteins were determined by the indirect immunoperoxidase technique after fixation with methanol and acetone. Biopsy materials for cultured keratinocytes, i.e., foreskin and hair follicles, contained the two major forms of cytochrome P450. In cultured keratinocytes derived from hair follicles the proteins were undetectable, whereas the keratinocytes derived from foreskin continued to express the two major forms of hepatic cytochrome P450. Cultured human fibroblasts and a human keratinocyte cell line (SVK14) showed staining similar to that of the foreskin keratinocytes. Cytochrome P450-9 was detectable only in human hepatocytes. The results indicate that, under the culture conditions applied, cultured human foreskin cells and the cell line SVK14 continue to express specific cytochrome P450 isoenzymes in culture, in contrast to hair follicle keratinocytes.

  17. Changes in the expression of Hepatic Cytochrome P450 Isoenzymes 2E1, 2B1/2, 4A, and 2C6 in mice infected with different levels of Schistosoma Mansoni Cercariae

    Sheweita, Salah A.

    2005-01-01

    Most xenobiotic agents are metabolized by cytochrome P450 system. In the present study, Western blotting was used to investigate the effect of different levels of Schistosoma Mansoni infection on the expression of somr cytochrome P450 isozymes (CYP 2E1, 2B1/2, 2C6, 4A) and to enzyme assay their related metabolic functions in mouse liver microsomes. Male mice were infected with 60, 120, 180, 300 and 600 Schistosoma Mansoni cercariae per mouse for 33 days and 60, 120, 180 and 300 cercariae/mouse with no change at the last level of Schistosoma Mansoni infection. Also the expression of CYP 4A was potentially induced at all levels of Schistosoma Mansoni infection. A significant induction of CYP 2B1/2 expression was observed at all levels of Schistosoma Mansoni infection with loss of signal at 180 cercariaea/mouse. In contrast, CYP 2C6 expression was induced at the first two levels and such expression was decreased at the last three levels. In addition, the infection of the mouse with 60, 120 and 180 cercariae/mouse decreased; [1] 7-methoxycoumarin O-demethylase activity by 36, 54 and 58% respectively; [2] 7-ethoxycoumarin O-deethylase activity by 33, 40 and 57% respectively; [3] coumarin hydroxlase activity by 33, 45 and 55% respectively. However, 300 and 600 cercariae/mouse induced: [1] 7-methoxycoumarin O-demethylase activity by 45 and 97% respectively: [2] 7-ethoxycoumarin O-deethylase activity by 26 and 90% respectively; [3] coumarin hydroxylase activity by 100 and 200% respectively. In addition, all levels of Schistosoma Mansoni infection decreased the sleeping time caused by hexobarital. It is concluded that different levels of Schistosoma Mansoni infection change the expression of different CYPisozymes and that these alterations could enhance the carcinogenicity of N-nitrosamines which is mainly dependent on CYP 2E1. The alterations in the expression of CYP 2E1, 4A and 2B1/2 isozymes as a result of Schistosoma Mansoni infection may change the therapeutic actions

  18. Mutagenic activation and detoxification of benzo[a]pyrene in vitro by hepatic cytochrome P450 1A1 and phase II enzymes in three meat-producing animals.

    Darwish, W; Ikenaka, Y; Eldaly, E; Ishizuka, M

    2010-01-01

    The mutagenic activation activity of hepatic microsomes from three meat-producing animals (cattle, deer and horses) was compared with those of rats as a reference species. In the Ames Salmonella typhimurium TA98 assay, the liver microsomes of all examined animals mutagenically activated benzo[a]pyrene, an ideal promutagens, in terms of production of histidine-independent revertant colonies. The microsomes of horses had the highest ability to produce revertant colonies of the examined animals under both low and high substrate concentrations. Inhibition of this mutagenic activity using alpha-naphthoflavone, anti-rat CYP1A1, CYP3A2 and CYP2E1 antibodies suggests that this activity was mainly because of CYP1A1 in these animals as well as in rats. The addition of co-factors for two phase II enzymes, microsomal UDP glucoronosyl transferase and cytosolic glutathione-S-transferase, reduced the production of the revertant colonies in a concentration-dependent manner. Interestingly, horses had the highest reduction rate among the examined animals, suggesting that phase II enzymes play a great role in producing a state of balance between the bioactivation and detoxification of xenobiotics in these meat-producing animals. This report is the first to investigate the mutagenic activation activity of the hepatic microsomes and the role of phase II enzymes against this activity in meat-producing animals. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  19. Hepatic Encephalopathy

    Full Text Available ... A Hepatitis B Hepatitis C Intrahepatic Cholestasis of Pregnancy (ICP) Jaundice In Newborns Diseases of the Liver ... A Hepatitis B Hepatitis C Intrahepatic Cholestasis of Pregnancy (ICP) Jaundice In Newborns Diseases of the Liver ...

  20. Viral Hepatitis

    ... Home A-Z Health Topics Viral hepatitis Viral hepatitis > A-Z Health Topics Viral hepatitis (PDF, 90 ... liver. Source: National Cancer Institute Learn more about hepatitis Watch a video. Learn who is at risk ...

  1. Hepatitis B

    ... B Entire Lesson Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For Veterans and the Public Veterans ... in their blood (sometimes referred to as the hepatitis B viral load) and an unusually high level of a ...

  2. Cytochrome P-450-catalyzed desaturation of valproic acid in vitro. Species differences, induction effects, and mechanistic studies

    Rettie, A.E.; Boberg, M.; Rettenmeier, A.W.; Baillie, T.A.

    1988-01-01

    The cytochrome P-450-mediated desaturation of valproic acid (VPA) to its hepatotoxic metabolite, 2-n-propyl-4-pentenoic acid (4-ene-VPA), was examined in liver microsomes from rats, mice, rabbits and humans. The highest substrate turnover was found with microsomes from rabbits (44.2 +/- 2.7 pmol of product/nmol P-450/15 min), while lower activities were observed in preparations from human, mouse, and rat liver, in that order. Pretreatment of animals with phenobarbital led to enhanced rates of formation of 4-ene-VPA in vitro and yielded induction ratios for desaturation ranging from 2.5 to 8.4, depending upon the species. Comparative studies in the rat showed that phenobarbital is a more potent inducer of olefin formation than either phenytoin or carbamazepine. The mechanism of the desaturation reaction was studied by inter- and intramolecular deuterium isotope effect experiments, which demonstrated that removal of a hydrogen atom from the subterminal C-4 position of VPA is rate limiting in the formation of both 4-ene- and 4-hydroxy-VPA. Hydroxylation at the neighboring C-5 position, on the other hand, was highly sensitive to deuterium substitution at that site, but not to deuteration at C-4. Based on these findings, it is proposed that 4-ene- and 4-hydroxy-VPA are products of a common P-450-dependent metabolic pathway, in which a carbon-centered free radical at C-4 serves as the key intermediate. 5-Hydroxy-VPA, in contrast, derives from an independent hydroxylation reaction

  3. Metabolism of styrene to styrene oxide and vinylphenols in cytochrome P450 2F2- and P450 2E1-knockout mouse liver and lung microsomes.

    Shen, Shuijie; Li, Lei; Ding, Xinxin; Zheng, Jiang

    2014-01-21

    Pulmonary toxicity of styrene is initiated by cytochromes P450-dependent metabolic activation. P450 2E1 and P450 2F2 are considered to be two main cytochrome P450 enzymes responsible for styrene metabolism in mice. The objective of the current study was to determine the correlation between the formation of styrene metabolites (i.e., styrene oxide and 4-vinylphenol) and pulmonary toxicity of styrene, using Cyp2e1- and Cyp2f2-null mouse models. A dramatic decrease in the formation of styrene glycol and 4-vinylphenol was found in Cyp2f2-null mouse lung microsomes relative to that in the wild-type mouse lung microsomes; however, no significant difference in the production of the styrene metabolites was observed between lung microsomes obtained from Cyp2e1-null and the wild-type mice. The knockout and wild-type mice were treated with styrene (6.0 mmol/kg, ip), and cell counts and LDH activity in bronchoalveolar lavage fluids were monitored to evaluate the pulmonary toxicity induced by styrene. Cyp2e1-null mice displayed a susceptibility to lung toxicity of styrene similar to that of the wild-type animals; however, Cyp2f2-null mice were resistant to styrene-induced pulmonary toxicity. In conclusion, both P450 2E1 and P450 2F2 are responsible for the metabolic activation of styrene. The latter enzyme plays an important role in styrene-induced pulmonary toxicity. Both styrene oxide and 4-vinylphenol are suggested to participate in the development of lung injury induced by styrene.

  4. Identification of human cytochrome P450s as autoantigens.

    Manns, M P; Johnson, E F

    1991-01-01

    Antimicrosomal antibodies in inflammatory liver diseases all seem to be directed against members of the cytochrome P450 family of proteins. These autoantigens seem to be genetically polymorphic, the autoantibodies are inhibitory, and the autoepitopes are generally conserved among species. Anti-P450 autoantibodies share these characteristics with other autoantibodies, for example, antinuclear antibodies in systemic lupus erythematosus. The identification of P450s as human autoantigens is clinically important. Diagnostic tests will be developed on the basis of cloned antigen, facilitating a better diagnosis of drug-induced and idiopathic autoimmune hepatitis. It is unknown what triggers autoantibody production against cytochrome P450 proteins. Furthermore, their pathogenetic role and thus their involvement in tissue destruction is unclear. In this context LKM1 autoantibodies may serve as a model. Although LKM1 antibodies are inhibitory, all LKM1 antibody-positive patients tested so far are extensive metabolizers for drug metabolism mediated by P450IID6 and express this protein in their livers. Thus, the inhibitory LKM1 autoantibody does not sufficiently penetrate through the intact liver cell membrane to inhibit enzyme function in vivo. Presumably, tissue destruction in autoimmune hepatitis is mediated by liver-infiltrating T lymphocytes. T lymphocytes have been cloned from liver tissue that specifically proliferate in the presence of recombinant cytochrome P450IID6. The construction of overlapping cDNA subclones is also valuable to identify immunodominant B cell as well as relevant T cell epitopes.

  5. The Role of Cytochromes P450 in Infection

    Elisavet Stavropoulou

    2018-01-01

    Full Text Available Cytochromes are expressed in many different tissues of the human body. They are found mostly in intestinal and hepatic tissues. Cytochromes P450 (CYPs are enzymes that oxidize substances using iron and are able to metabolize a large variety of xenobiotic substances. CYP enzymes are linked to a wide array of reactions including and O-dealkylation, S-oxidation, epoxidation, and hydroxylation. The activity of the typical P450 cytochrome is influenced by a variety of factors, such as genus, environment, disease state, herbicide, alcohol, and herbal medications. However, diet seems to play a major role. The mechanisms of action of dietary chemicals, macro- and micronutrients on specific CYP isoenzymes have been extensively studied. Dietary modulation has effects upon the metabolism of xenobiotics. Cytochromes harbor intra- or interindividual and intra- or interethnic genetic polymorphisms. Bacteria were shown to express CYP-like genes. The tremendous metabolic activity of the microbiota is associated to its abundant pool of CYP enzymes, which catalyze phase I and II reactions in drug metabolism. Disease states, intestinal disturbances, aging, environmental toxic effects, chemical exposures or nutrition modulate the microbial metabolism of a drug before absorption. A plethora of effects exhibited by most of CYP enzymes can resemble those of proinflammatory cytokines and IFNs. Moreover, they are involved in the initiation and persistence of pathologic pain by directly activating sensory neurons and inflammatory cytokines.

  6. The cytochrome p450 homepage.

    Nelson, David R

    2009-10-01

    The Cytochrome P450 Homepage is a universal resource for nomenclature and sequence information on cytochrome P450 ( CYP ) genes. The site has been in continuous operation since February 1995. Currently, naming information for 11,512 CYPs are available on the web pages. The P450 sequences are manually curated by David Nelson, and the nomenclature system conforms to an evolutionary scheme such that members of CYP families and subfamilies share common ancestors. The organisation and content of the Homepage are described.

  7. Hepatic Encephalopathy

    Full Text Available ... 1 (von Gierke) Hemochromatosis Hepatic Encephalopathy Hepatitis A Hepatitis B Hepatitis C Intrahepatic Cholestasis of Pregnancy (ICP) Jaundice ... diseases. What are the common causes of cirrhosis? Hepatitis B & C Alcohol-related Liver Disease Non-alcoholic Fatty ...

  8. [Effects of berberine on the recovery of rat liver xenobiotic-metabolizing enzymes after partial hepatectomy].

    Zverinsky, I V; Zverinskaya, H G; Sutsko, I P; Telegin, P G; Shlyahtun, A G

    2015-01-01

    We have studied the effect of berberine on the recovery processes of liver xenobiotic-metabolizing function during its compensatory growth after 70% partial hepatectomy. It was found the hepatic ability to metabolize foreign substances are not restored up to day 8. Administration of berberine (10 mg/kg intraperitoneally) for 6 days led to normalization of both cytochrome P450-dependent and flavin-containing monooxygenases. It is suggested that in the biotransformation of berberine involved not only cytochrome P450, but also flavin-containing monooxygenases.

  9. Cytochrome b5 and NADH cytochrome b5 reductase: genotype-phenotype correlations for hydroxylamine reduction.

    Sacco, James C; Trepanier, Lauren A

    2010-01-01

    NADH cytochrome b5 reductase (b5R) and cytochrome b5 (b5) catalyze the reduction of sulfamethoxazole hydroxylamine (SMX-HA), which can contribute to sulfonamide hypersensitivity, to the parent drug sulfamethoxazole. Variability in hydroxylamine reduction could thus play a role in adverse drug reactions. The aim of this study was to characterize variability in SMX-HA reduction in 111 human livers, and investigate its association with single nucleotide polymorphisms (SNPs) in b5 and b5R cDNA. Liver microsomes were assayed for SMX-HA reduction activity, and b5 and b5R expression was semiquantified by immunoblotting. The coding regions of the b5 (CYB5A) and b5R (CYB5R3) genes were resequenced. Hepatic SMX-HA reduction displayed a 19-fold range of individual variability (0.06-1.11 nmol/min/mg protein), and a 17-fold range in efficiency (Vmax/Km) among outliers. SMX-HA reduction was positively correlated with b5 and b5R protein content (Phydroxylamine reduction activities, these low-frequency cSNPs seem to only minimally impact overall observed phenotypic variability. Work is underway to characterize polymorphisms in other regions of these genes to further account for individual variability in hydroxylamine reduction.

  10. Hepatitis Vaccines

    Ogholikhan, Sina; Schwarz, Kathleen B.

    2016-01-01

    Viral hepatitis is a serious health problem all over the world. However, the reduction of the morbidity and mortality due to vaccinations against hepatitis A and hepatitis B has been a major component in the overall reduction in vaccine preventable diseases. We will discuss the epidemiology, vaccine development, and post-vaccination effects of the hepatitis A and B virus. In addition, we discuss attempts to provide hepatitis D vaccine for the 350 million individuals infected with hepatitis B ...

  11. Hepatic Encephalopathy

    Full Text Available ... Donate Today Enroll in 123 What is Hepatic Encephalopathy? Hepatic Encephalopathy, sometimes referred to as portosystemic encephalopathy or PSE, is a condition that causes temporary ...

  12. Role of cytochrome P450 in drug interactions

    Bibi Zakia

    2008-10-01

    Full Text Available Abstract Drug-drug interactions have become an important issue in health care. It is now realized that many drug-drug interactions can be explained by alterations in the metabolic enzymes that are present in the liver and other extra-hepatic tissues. Many of the major pharmacokinetic interactions between drugs are due to hepatic cytochrome P450 (P450 or CYP enzymes being affected by previous administration of other drugs. After coadministration, some drugs act as potent enzyme inducers, whereas others are inhibitors. However, reports of enzyme inhibition are very much more common. Understanding these mechanisms of enzyme inhibition or induction is extremely important in order to give appropriate multiple-drug therapies. In future, it may help to identify individuals at greatest risk of drug interactions and adverse events.

  13. NADPH–Cytochrome P450 Oxidoreductase: Roles in Physiology, Pharmacology, and Toxicology

    Ding, Xinxin; Wolf, C. Roland; Porter, Todd D.; Pandey, Amit V.; Zhang, Qing-Yu; Gu, Jun; Finn, Robert D.; Ronseaux, Sebastien; McLaughlin, Lesley A.; Henderson, Colin J.; Zou, Ling; Flück, Christa E.

    2013-01-01

    This is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 2012 meeting in San Diego, California, on April 25, 2012. The symposium speakers summarized and critically evaluated our current understanding of the physiologic, pharmacological, and toxicological roles of NADPH–cytochrome P450 oxidoreductase (POR), a flavoprotein involved in electron transfer to microsomal cytochromes P450 (P450), cytochrome b5, squalene mono-oxygenase, and heme oxygenase. Considerable insight has been derived from the development and characterization of mouse models with conditional Por deletion in particular tissues or partial suppression of POR expression in all tissues. Additional mouse models with global or conditional hepatic deletion of cytochrome b5 are helping to clarify the P450 isoform- and substrate-specific influences of cytochrome b5 on P450 electron transfer and catalytic function. This symposium also considered studies using siRNA to suppress POR expression in a hepatoma cell–culture model to explore the basis of the hepatic lipidosis phenotype observed in mice with conditional deletion of Por in liver. The symposium concluded with a strong translational perspective, relating the basic science of human POR structure and function to the impacts of POR genetic variation on human drug and steroid metabolism. PMID:23086197

  14. Hepatitis C: Managing Pain

    ... Pain: Entire Lesson Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For Veterans and the Public Veterans and the Public Home Hepatitis A Hepatitis B Hepatitis C Hepatitis C Home Getting ...

  15. Novel extrahepatic cytochrome P450s

    Karlgren, Maria; Miura, Shin-ichi; Ingelman-Sundberg, Magnus

    2005-01-01

    The cytochrome P450 enzymes are highly expressed in the liver and are involved in the metabolism of xenobiotics. Because of the initiatives associated with the Human Genome Project, a great progress has recently been seen in the identification and characterization of novel extrahepatic P450s, including CYP2S1, CYP2R1, CYP2U1 and CYP2W1. Like the hepatic enzymes, these P450s may play a role in the tissue-specific metabolism of foreign compounds, but they may also have important endogenous functions. CYP2S1 has been shown to metabolize all-trans retinoic acid and CYP2R1 is a major vitamin D 25-hydroxylase. Regarding their metabolism of xenobiotics, much remains to be established, but CYP2S1 metabolizes naphthalene and it is likely that these P450s are responsible for metabolic activation of several different kinds of xenobiotic chemicals and contribute to extrahepatic toxicity and carcinogenesis

  16. One-electron oxidation of diclofenac by human cytochrome P450s as a potential bioactivation mechanism for formation of 2'-(glutathion-S-yl)-deschloro-diclofenac.

    Boerma, Jan Simon; Vermeulen, Nico P E; Commandeur, Jan N M

    2014-01-25

    Reactive metabolites have been suggested to play a role in the idiosyncratic hepatotoxicity observed with diclofenac (DF). By structural identification of the GSH conjugates formed after P450-catalyzed bioactivation of DF, it was shown that three types of reactive intermediates were formed: p-benzoquinone imines, o-imine methide and arene-oxide. Recently, detection of 2'-(glutathion-S-yl)-deschloro-diclofenac (DDF-SG), resulting from chlorine substitution, suggested the existence of a fourth type of P450-dependent reactive intermediate whose inactivation by GSH is completely dependent on presence of glutathione S-transferase. In this study, fourteen recombinant cytochrome P450s and three flavin-containing monooxygenases were tested for their ability to produce oxidative DF metabolites and their corresponding GSH conjugates. Concerning the hydroxymetabolites and their GSH conjugates, results were consistent with previous studies. Unexpectedly, all tested recombinant P450s were able to form DDF-SG to almost similar extent. DDF-SG formation was found to be partially independent of NADPH and even occurred by heat-inactivated P450. However, product formation was fully dependent on both GSH and glutathione-S-transferase P1-1. DDF-SG formation was also observed in reactions with horseradish peroxidase in absence of hydrogen peroxide. Because DDF-SG was not formed by free iron, it appears that DF can be bioactivated by iron in hemeproteins. This was confirmed by DDF-SG formation by other hemeproteins such as hemoglobin. As a mechanism, we propose that DF is subject to heme-dependent one-electron oxidation. The resulting nitrogen radical cation, which might activate the chlorines of DF, then undergoes a GST-catalyzed nucleophilic aromatic substitution reaction in which the chlorine atom of the DF moiety is replaced by GSH. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  17. Hepatic Encephalopathy

    Full Text Available ... friend, spouse, life partner, parent, sibling or other family member. What is HE? Hepatic Encephalopathy, sometimes referred ... disease is. It’s important for you and your family to become familiar with the signs of Hepatic ...

  18. Hepatic Encephalopathy

    Full Text Available ... Your Story Spread the Word Give While You Shop Contact Us Donate Now Hepatic Encephalopathy Back Hepatic ... Your Story Spread the Word Give While You Shop Contact Us Donate Now Help ALF Improve This ...

  19. Hepatic Encephalopathy

    Full Text Available ... Now Hepatic Encephalopathy Back Hepatic Encephalopathy is a brain disorder that develops in some individuals with liver ... is a condition that causes temporary worsening of brain function in people with advanced liver disease. When ...

  20. Alcohol and Hepatitis

    ... Home » Living with Hepatitis » Daily Living: Alcohol Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... heavy drinking, most heavy drinkers have developed cirrhosis. Hepatitis C and cirrhosis In general, someone with hepatitis ...

  1. Hepatitis C: Treatment

    ... Public Home » Hepatitis C » Hepatitis C Treatment Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... Enter ZIP code here Enter ZIP code here Hepatitis C Treatment for Veterans and the Public Treatment ...

  2. In vivo cytochrome P450 activity alterations in diabetic nonalcoholic steatohepatitis mice

    Li, Hui; Clarke, John D.; Dzierlenga, Anika L.; Bear, John; Goedken, Michael J.; Cherrington, Nathan J.

    2016-01-01

    Nonalcoholic steatohepatitis (NASH) has been identified as a source of significant interindividual variation in drug metabolism. A previous ex vivo study demonstrated significant changes in hepatic Cytochrome P450 (CYP) activity in human NASH. This study evaluated the in vivo activities of multiple CYP isoforms simultaneously in prominent diabetic NASH mouse models. The pharmacokinetics of CYP selective substrates: caffeine, losartan, and omeprazole changed significantly in a diabetic NASH mo...

  3. Hepatitis C

    ... an inflammation of the liver. One type, hepatitis C, is caused by the hepatitis C virus (HCV). It usually spreads through contact with ... childbirth. Most people who are infected with hepatitis C don't have any symptoms for years. If ...

  4. Hepatic Encephalopathy

    Full Text Available ... Caregiver Support Caregiver Stories Home › What is Hepatic Encephalopathy? Why Your Liver is Important The Connection Between HE and Liver ... Why it’s Important to Treat HE Symptoms of Liver Failure Glossary of terms ... is Hepatic Encephalopathy? Hepatic Encephalopathy, sometimes referred to as portosystemic encephalopathy ...

  5. Hepatic Encephalopathy

    ... Caregiver Support Caregiver Stories Home › What is Hepatic Encephalopathy? Why Your Liver is Important The Connection Between HE and Liver ... Why it’s Important to Treat HE Symptoms of Liver Failure Glossary of terms ... is Hepatic Encephalopathy? Hepatic Encephalopathy, sometimes referred to as portosystemic encephalopathy ...

  6. Hepatitis A

    ... is an inflammation of the liver. One type, hepatitis A, is caused by the hepatitis A virus (HAV). The disease spreads through contact with ... suggest medicines to help relieve your symptoms. The hepatitis A vaccine can prevent HAV. Good hygiene can also ...

  7. Hypoksisk hepatitis

    Amadid, Hanan; Schiødt, Frank Vinholt

    2014-01-01

    Hypoxic hepatitis (HH), also known as ischaemic hepatitis or shock liver, is an acute liver injury caused by hepatic hypoxia. Cardiac failure, respiratory failure and septic shock are the main underlying conditions. In each of these conditions, several haemodynamic mechanisms lead to hepatic...... hypoxia. A shock state is observed in only 50% of cases. Thus, shock liver and ischaemic hepatitis are misnomers. HH can be a diagnostic pitfall but the diagnosis can be established when three criteria are met. Prognosis is poor and prompt identification and treatment of the underlying conditions...

  8. Human HepaRG Cells can be Cultured in Hanging-drop Plates for Cytochrome P450 Induction and Function Assays.

    Murayama, Norie; Usui, Takashi; Slawny, Nicky; Chesné, Christophe; Yamazaki, Hiroshi

    2015-01-01

    Recent guidance/guidelines for industry recommend that cytochrome P450 induction can be assessed using human hepatocyte enzyme activity and/or mRNA levels to evaluate potential drug- drug interactions. To evaluate time-dependent cytochrome P450 induction precisely, induction of CYP1A2, CYP2B6, and CYP3A4 mRNA was confirmed (>2-fold) by the treatment with omeprazole, phenobarbital, and rifampicin, respectively, for 24 or 48 h on day 3 from the start of culture. After 24 h, the fold induction of CYP1A2 with 3.6 and 1.8x10(4) HepaRG cells per well was lower than that for 7.2x10(4) cells. CYP1A2 induction levels at 24 h were higher than those after 48 h. In contrast, higher CYP2B6 inductions were confirmed after 48 h exposure than after 24 h, independent of the number of cells per well. To help reduce the use of human cryopreserved hepatocytes, typical P450-dependent enzyme activities were investigated in human HepaRG cells cultured in commercial hanging-drop plates. Newly designed 96-well hanging-drop plates were capable of maintaining human CYP3A-dependent midazolam hydroxylation activities for up to 4 days using only 10% of the recommended initial 7.2x10(4) cells per well. Favorable HepaRG function using hanging-drop plates was confirmed by detecting 1'- hydroxymidazolam O-glucuronide on day 3, suggesting an improvement over traditional control plates in which this metabolite can be detected for 24-well plates. These results suggest that the catalytic function and/or induction of CYP1A2, CYP2B6, and CYP3A4 can be readily assessed with reduced numbers of starting HepaRG cells cultured in three-dimensional cultures in drops prepared with hanging-drop plates.

  9. Hepatitis A through E (Viral Hepatitis)

    ... Treatment Eating, Diet, & Nutrition Clinical Trials Wilson Disease Hepatitis (Viral) View or Print All Sections What is Viral Hepatitis? Viral hepatitis is an infection that causes liver inflammation ...

  10. Hepatitis Vaccines

    Sina Ogholikhan

    2016-03-01

    Full Text Available Viral hepatitis is a serious health problem all over the world. However, the reduction of the morbidity and mortality due to vaccinations against hepatitis A and hepatitis B has been a major component in the overall reduction in vaccine preventable diseases. We will discuss the epidemiology, vaccine development, and post-vaccination effects of the hepatitis A and B virus. In addition, we discuss attempts to provide hepatitis D vaccine for the 350 million individuals infected with hepatitis B globally. Given the lack of a hepatitis C vaccine, the many challenges facing the production of a hepatitis C vaccine will be shown, along with current and former vaccination trials. As there is no current FDA-approved hepatitis E vaccine, we will present vaccination data that is available in the rest of the world. Finally, we will discuss the existing challenges and questions facing future endeavors for each of the hepatitis viruses, with efforts continuing to focus on dramatically reducing the morbidity and mortality associated with these serious infections of the liver.

  11. Hepatitis Vaccines

    Ogholikhan, Sina; Schwarz, Kathleen B.

    2016-01-01

    Viral hepatitis is a serious health problem all over the world. However, the reduction of the morbidity and mortality due to vaccinations against hepatitis A and hepatitis B has been a major component in the overall reduction in vaccine preventable diseases. We will discuss the epidemiology, vaccine development, and post-vaccination effects of the hepatitis A and B virus. In addition, we discuss attempts to provide hepatitis D vaccine for the 350 million individuals infected with hepatitis B globally. Given the lack of a hepatitis C vaccine, the many challenges facing the production of a hepatitis C vaccine will be shown, along with current and former vaccination trials. As there is no current FDA-approved hepatitis E vaccine, we will present vaccination data that is available in the rest of the world. Finally, we will discuss the existing challenges and questions facing future endeavors for each of the hepatitis viruses, with efforts continuing to focus on dramatically reducing the morbidity and mortality associated with these serious infections of the liver. PMID:26978406

  12. Feature Hepatitis: Hepatitis Can Strike Anyone

    ... Navigation Bar Home Current Issue Past Issues Feature Hepatitis Hepatitis Can Strike Anyone Past Issues / Spring 2009 Table ... from all walks of life are affected by hepatitis, especially hepatitis C, the most common form of ...

  13. Hepatic Encephalopathy

    Full Text Available ... Plan Long-Term Considerations Patient Support Finding Support Services Peer Support Groups Financial Assistance Support for My ... is Hepatic Encephalopathy? Why Your Liver is ...

  14. Travelers' Health: Hepatitis C

    ... Chapter 3 - Hepatitis B Chapter 3 - Hepatitis E Hepatitis C Deborah Holtzman INFECTIOUS AGENT Hepatitis C virus ( ... mother to child. Map 3-05. Prevalence of hepatitis C virus infection 1 PDF Version (printable) 1 ...

  15. Travelers' Health: Hepatitis A

    ... 3 - Helminths, Soil-Transmitted Chapter 3 - Hepatitis B Hepatitis A Noele P. Nelson INFECTIOUS AGENT Hepatitis A ... hepatitis/HAV Table 3-02. Vaccines to prevent hepatitis A VACCINE TRADE NAME (MANUFACTURER) AGE (Y) DOSE ...

  16. Hepatitis (For Parents)

    ... Staying Safe Videos for Educators Search English Español Hepatitis KidsHealth / For Parents / Hepatitis Print en español Hepatitis What Is Hepatitis? Hepatitis is an inflammation of the liver. The ...

  17. Travelers' Health: Hepatitis B

    ... Chapter 3 - Hepatitis A Chapter 3 - Hepatitis C Hepatitis B Francisco Averhoff INFECTIOUS AGENT Hepatitis B virus ( ... progression of disease. Map 3-04. Prevalence of hepatitis B virus infection 1 PDF Version (printable) 1 ...

  18. Hepatitis C: Clinical Trials

    ... and Public Home » Hepatitis C » Treatment Decisions Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... can I find out about participating in a hepatitis C clinical trial? Many trials are being conducted ...

  19. Hepatitis C: Mental Health

    ... the Public Home Hepatitis A Hepatitis B Hepatitis C Hepatitis C Home Getting Tested Just Diagnosed Treatment Choice Program ... Pain Mental Health Sex and Sexuality (for Hepatitis C) Success Stories FAQs For Health Care Providers Provider ...

  20. Short-Term Effects of Nose-Only Cigarette Smoke Exposure on Glutathione Redox Homeostasis, Cytochrome P450 1A1/2 and Respiratory Enzyme Activities in Mice Tissues

    Haider Raza

    2013-05-01

    Full Text Available Background/Aims: The components of cigarette smoke (CS have been implicated in the development of cancer as well as in cardiopulmonary diseases. We have previously reported increased oxidative stress in rat tissues induced by tobacco-specific toxins nicotine and 4-(N-methyl-N-nitrosamino-1-(3-pyridyl-1-butanone (NNK. Recently, we have also shown increased oxidative stress and associated inflammatory responses in various tissues after exposure to cigarette smoke. Methods: In this study, we have further investigated the effects of nose-only cigarette smoke exposure on mitochondrial functions and glutathione-dependent redox metabolism in tissues of BALB/C mice. Liver, kidney, heart and lung tissues were analyzed for oxidative stress, glutathione (GSH and cytochrome P450 dependent enzyme activities and mitochondrial functions after exposure to smoke generated by 9 cigarettes/day for 4 days. Control mice were exposed to air only. Results: An increase in oxidative stress as observed by increased production of reactive oxygen species (ROS and altered GSH metabolism was apparent in all the tissues, but lung and heart appeared to be the main targets. Increased expression and activity of CYP450 1A1 and 1A2 were also observed in the tissues after exposure to cigarette smoke. Mitochondrial respiratory dysfunction in the tissues, as observed by alterations in the activities of Complex I and IV enzymes, was also observed after exposure to cigarette smoke. SDS-PAGE and Western blot results also indicate that alterations in the expression of enzyme proteins were in accordance with the changes in their catalytic functions. Conclusion: These results suggest that even short term exposure of cigarette smoke have adverse effects on mitochondrial functions and redox homeostasis in tissues which may progress to further complications associated with chronic smoking.

  1. Alcoholic Hepatitis

    ... yellow color. Confusion, drowsiness and slurred speech (hepatic encephalopathy). A damaged liver has trouble removing toxins from your body. The ... of toxins can damage your brain. Severe hepatic encephalopathy can result in ... of the liver frequently leads to liver failure. Kidney failure. A ...

  2. Development of cytochrome P450 2D6-specific LKM-autoantibodies following liver transplantation for Wilson's disease -- possible association with a steroid-resistant transplant rejection episode.

    Lohse, A W; Obermayer-Straub, P; Gerken, G; Brunner, S; Altes, U; Dienes, H P; Manns, M P; Meyer zum Büschenfelde, K H

    1999-07-01

    Antibodies to cytochrome P450 2D6, also known as LKM1-autoantibodies, are characteristic for a subgroup of patients with autoimmune hepatitis, but can also occasionally be found in hepatitis C. We observed the occurrence of LKM1-autoantibodies 4 months after liver transplantation for Wilson's disease, in close association with a steroid-resistant rejection episode, in the absence of evidence for autoimmune hepatitis or hepatitis C. Sera from several time points prior to and following transplantation were tested for LKM-reactivity by immunofluorescence, ELISA and Western blotting. Antigen specificity was confirmed by Western blotting analysis on different cytochrome P450 isoenzymes. The absence of viral hepatitis C and hepatitis G virus infection was confirmed by polymerase chain reaction. The serum of the organ donor was also tested. All the sera prior to transplantation and up to 4 months after transplantation were LKM-negative by all assay systems used. In the course of a steroid-resistant rejection episode at this time, the patient developed LKM antibodies at high titre (70% in inhibition ELISA) and has remained positive since (now more than 4 years). Reactivity was exclusively to the cytochrome isoenzyme 2D6. Hepatitis C infection never occurred, but hepatitis G was transiently present many years prior to transplantation. The donor serum was negative for all autoantibodies and for hepatitis C and G virus infection. We here describe a patient developing LKM1-autoantibodies without evidence of autoimmune or viral hepatitis. The close temporal association with a transplant rejection episode suggests immunological mechanisms of rejection together with hepatocellular injury as a pathogenetic mechanism.

  3. Cytochrome P450 humanised mice

    Gonzalez Frank J

    2004-05-01

    Full Text Available Abstract Humans are exposed to countless foreign compounds, typically referred to as xenobiotics. These can include clinically used drugs, environmental pollutants, food additives, pesticides, herbicides and even natural plant compounds. Xenobiotics are metabolised primarily in the liver, but also in the gut and other organs, to derivatives that are more easily eliminated from the body. In some cases, however, a compound is converted to an electrophile that can cause cell toxicity and transformation leading to cancer. Among the most important xenobiotic-metabolising enzymes are the cytochromes P450 (P450s. These enzymes represent a superfamily of multiple forms that exhibit marked species differences in their expression and catalytic activities. To predict how humans will metabolise xenobiotics, including drugs, human liver extracts and recombinant P450s have been used. New humanised mouse models are being developed which will be of great value in the study of drug metabolism, pharmacokinetics and pharmacodynamics in vivo, and in carrying out human risk assessment of xenobiotics. Humanised mice expressing CYP2D6 and CYP3A4, two major drug-metabolising P450s, have revealed the feasibility of this approach.

  4. Cytochrome P450 humanised mice

    2004-01-01

    Humans are exposed to countless foreign compounds, typically referred to as xenobiotics. These can include clinically used drugs, environmental pollutants, food additives, pesticides, herbicides and even natural plant compounds. Xenobiotics are metabolised primarily in the liver, but also in the gut and other organs, to derivatives that are more easily eliminated from the body. In some cases, however, a compound is converted to an electrophile that can cause cell toxicity and transformation leading to cancer. Among the most important xenobiotic-metabolising enzymes are the cytochromes P450 (P450s). These enzymes represent a superfamily of multiple forms that exhibit marked species differences in their expression and catalytic activities. To predict how humans will metabolise xenobiotics, including drugs, human liver extracts and recombinant P450s have been used. New humanised mouse models are being developed which will be of great value in the study of drug metabolism, pharmacokinetics and pharmacodynamics in vivo, and in carrying out human risk assessment of xenobiotics. Humanised mice expressing CYP2D6 and CYP3A4, two major drug-metabolising P450s, have revealed the feasibility of this approach. PMID:15588489

  5. Heme exporter FLVCR1a regulates heme synthesis and degradation and controls activity of cytochromes P450.

    Vinchi, Francesca; Ingoglia, Giada; Chiabrando, Deborah; Mercurio, Sonia; Turco, Emilia; Silengo, Lorenzo; Altruda, Fiorella; Tolosano, Emanuela

    2014-05-01

    The liver has one of the highest rates of heme synthesis of any organ. More than 50% of the heme synthesized in the liver is used for synthesis of P450 enzymes, which metabolize exogenous and endogenous compounds that include natural products, hormones, drugs, and carcinogens. Feline leukemia virus subgroup C cellular receptor 1a (FLVCR1a) is plasma membrane heme exporter that is ubiquitously expressed and controls intracellular heme content in hematopoietic lineages. We investigated the role of Flvcr1a in liver function in mice. We created mice with conditional disruption of Mfsd7b, which encodes Flvcr1a, in hepatocytes (Flvcr1a(fl/fl);alb-cre mice). Mice were analyzed under basal conditions, after phenylhydrazine-induced hemolysis, and after induction of cytochromes P450 synthesis. Livers were collected and analyzed by histologic, quantitative real-time polymerase chain reaction, and immunoblot analyses. Hepatic P450 enzymatic activities were measured. Flvcr1a(fl/fl);alb-cre mice accumulated heme and iron in liver despite up-regulation of heme oxygenase 1, ferroportin, and ferritins. Hepatic heme export activity of Flvcr1a was closely associated with heme biosynthesis, which is required to sustain cytochrome induction. Upon cytochromes P450 stimulation, Flvcr1a(fl/fl);alb-cre mice had reduced cytochrome activity, associated with accumulation of heme in hepatocytes. The expansion of the cytosolic heme pool in these mice was likely responsible for the early inhibition of heme synthesis and increased degradation of heme, which reduced expression and activity of cytochromes P450. In livers of mice, Flvcr1a maintains a free heme pool that regulates heme synthesis and degradation as well as cytochromes P450 expression and activity. These findings have important implications for drug metabolism. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

  6. Heme Exporter FLVCR1a Regulates Heme Synthesis and Degradation and Controls Activity of Cytochromes P450

    Vinchi, Francesca; Ingoglia, Giada; Chiabrando, Deborah; Mercurio, Sonia; Turco, Emilia; Silengo, Lorenzo; Altruda, Fiorella; Tolosano, Emanuela

    2014-01-01

    Background & Aims The liver has one of the highest rates of heme synthesis of any organ. More than 50% of the heme synthesized in the liver is used for synthesis of P450 enzymes, which metabolize exogenous and endogenous compounds that include natural products, hormones, drugs, and carcinogens. Feline leukemia virus subgroup C cellular receptor 1a (FLVCR1a) is plasma membrane heme exporter that is ubiquitously expressed and controls intracellular heme content in hematopoietic lineages. We investigated the role of Flvcr1a in liver function in mice. Methods We created mice with conditional disruption of Mfsd7b, which encodes Flvcr1a, in hepatocytes (Flvcr1afl/fl;alb-cre mice). Mice were analyzed under basal conditions, after phenylhydrazine-induced hemolysis, and after induction of cytochromes P450 synthesis. Livers were collected and analyzed by histologic, quantitative real-time polymerase chain reaction, and immunoblot analyses. Hepatic P450 enzymatic activities were measured. Results Flvcr1afl/fl;alb-cre mice accumulated heme and iron in liver despite up-regulation of heme oxygenase 1, ferroportin, and ferritins. Hepatic heme export activity of Flvcr1a was closely associated with heme biosynthesis, which is required to sustain cytochrome induction. Upon cytochromes P450 stimulation, Flvcr1afl/fl;alb-cre mice had reduced cytochrome activity, associated with accumulation of heme in hepatocytes. The expansion of the cytosolic heme pool in these mice was likely responsible for the early inhibition of heme synthesis and increased degradation of heme, which reduced expression and activity of cytochromes P450. Conclusions In livers of mice, Flvcr1a maintains a free heme pool that regulates heme synthesis and degradation as well as cytochromes P450 expression and activity. These findings have important implications for drug metabolism. PMID:24486949

  7. Hepatic Encephalopathy

    Full Text Available ... to continue to work to my full capacity? Will I be able to drive? Patient Stories Angie M. Caregiver for Brother Charles DiAngelo Hepatic Encephalopathy Jason Dedmon Alcohol-related Cirrhosis ...

  8. Hepatic Encephalopathy

    Full Text Available ... your body when your liver isn’t working well, it may affect your brain and cause HE. ... it apparent that the liver is not doing well. These could be the symptoms of Hepatic Encephalopathy ( ...

  9. Hepatic Encephalopathy

    Full Text Available ... bad. It sends the good things – such as vitamins and nutrients – into your bloodstream for your body ... for Wife Joyce O. Caregiver for Mother Lynette K. Hepatic Encephalopathy Samantha W. Caregiver for Husband Stan ...

  10. Hepatic Encephalopathy

    Full Text Available ... Get Worse? How is HE Diagnosed? Prior to Treatment Who treats HE? Preparing for your Medical Appointment Hepatic Encephalopathy Treatment Options Treatment Basics Treatment Medications Importance of Adhering ...

  11. Hepatic Encephalopathy

    Full Text Available ... become familiar with the signs of Hepatic Encephalopathy so you can tell your doctor right away if ... with continuous treatment, HE can usually be controlled. So it’s important to tell your doctor about any ...

  12. Hepatic Encephalopathy

    Full Text Available ... build-up and painful swelling of the legs (edema) and abdomen (ascites) or hepatic encephalopathy. For more ... build up and painful swelling of the legs (edema) and abdomen (ascites) Bruising and bleeding easily Enlarged ...

  13. Hepatic Encephalopathy

    Full Text Available ... to Treatment Who treats HE? Preparing for your Medical Appointment Hepatic Encephalopathy Treatment Options Treatment Basics Treatment ... treatment. Being a fully-informed participant in your medical care is an important factor in staying as ...

  14. Hepatic Encephalopathy

    Full Text Available ... Hepatic Encephalopathy so you can tell your doctor right away if you think you may have it. ... American Liver Foundation © 2018 American Liver Foundation. All rights reserved. Funding for the HE123 - Diagnosis, Treatment and ...

  15. Hepatic Encephalopathy

    Full Text Available ... important for you and your family to become familiar with the signs of Hepatic Encephalopathy so you ... team evaluates the person’s overall physical and mental health, plan to pay for transplant related medical expenses, ...

  16. Hepatic Encephalopathy

    Full Text Available ... Symptoms to look for Caregiver Support Caregiver Stories Home › What is Hepatic Encephalopathy? Why Your Liver is ... questions about HE, one step at a time. Home About Us Ways to Give Contact Us Privacy ...

  17. Hepatic Encephalopathy

    Full Text Available ... responsible for the daily needs of another person. Caregivers can be a friend, spouse, life partner, parent, sibling or other family member. What is HE? Hepatic Encephalopathy, sometimes referred to as ...

  18. Hepatitis C

    ... viral load (the amount of HCV in your blood), imaging tests, and biopsy results. Treatment is especially important for people who are showing signs liver fibrosis or scarring. Medicines used to treat hepatitis C ...

  19. Hepatic Encephalopathy

    Full Text Available ... that can be corrected . It may also occur as part of a chronic problem from liver disease ... worse over time. Hepatic Encephalopathy, sometimes referred to as portosystemic encephalopathy or PSE, is a condition that ...

  20. Hepatitis A

    ... Acute liver failure requires a stay in the hospital for monitoring and treatment. Some people with acute liver failure may need a liver transplant. Prevention The hepatitis A vaccine can prevent infection with the virus. The vaccine is typically given ...

  1. Hepatic Encephalopathy

    Full Text Available ... OVERVIEW Donate Now Join an Event Volunteer Your Time The Legacy Society Make Gifts of Stock Donate ... problem from liver disease that gets worse over time. Hepatic Encephalopathy, sometimes referred to as portosystemic encephalopathy ...

  2. Hepatic Encephalopathy

    Full Text Available ... Patient Advisory Council Media Center Careers How You Can Help OVERVIEW Donate Now Join an Event Volunteer ... Hepatic Encephalopathy is a short-term problem that can be corrected . It may also occur as part ...

  3. Hepatic Encephalopathy

    Full Text Available ... People ALF Near You Events ALF Blogs Financial Information Policies Advocacy Patient Advisory Council Media Center Careers ... and abdomen (ascites) or hepatic encephalopathy. For more information about cirrhosis of the liver and symptoms, call ...

  4. Hepatic Encephalopathy

    Full Text Available ... Disease (NAFLD) & Non-alcoholic Steatohepatitis (NASH) Autoimmune Hepatitis Bile duct disease such as Primary Biliary Cirrhosis (PBC) ... spleen (splenomegaly) Stone-like particles in gallbladder and bile duct (gallstones) Liver cancer (hepatocellular carcinoma) Chronic liver ...

  5. Autoimmune Hepatitis

    ... hepatitis is the most common form in North America. Type 1 can occur at any age; however, ... eastern time, M-F Follow Us NIH… Turning Discovery Into Health ® Research & Funding Current Funding Opportunities Research ...

  6. Hepatic Encephalopathy

    Full Text Available ... Hepatic Encephalopathy Treatment Options Treatment Basics Treatment Medications Importance of Adhering to Your Treatment Plan Long-Term Considerations Patient Support Finding Support Services Peer Support Groups Financial Assistance Support for My Loved Ones Resources Find ...

  7. Hepatic Encephalopathy

    Full Text Available ... Hepatic Encephalopathy so you can tell your doctor right away if you think you may have it. ... Site Map © COPYRIGHT 2017 AMERICAN LIVER FOUNDATION. ALL RIGHTS RESERVED. Your Liver Overview

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  8. Hepatic Encephalopathy

    Full Text Available ... is a condition that causes temporary worsening of brain function in people with advanced liver disease. When ... travel through your body until they reach your brain, causing mental and physical symptoms of HE. Hepatic ...

  9. Cytochrome c1 exhibits two binding sites for cytochrome c in plants.

    Moreno-Beltrán, Blas; Díaz-Quintana, Antonio; González-Arzola, Katiuska; Velázquez-Campoy, Adrián; De la Rosa, Miguel A; Díaz-Moreno, Irene

    2014-10-01

    In plants, channeling of cytochrome c molecules between complexes III and IV has been purported to shuttle electrons within the supercomplexes instead of carrying electrons by random diffusion across the intermembrane bulk phase. However, the mode plant cytochrome c behaves inside a supercomplex such as the respirasome, formed by complexes I, III and IV, remains obscure from a structural point of view. Here, we report ab-initio Brownian dynamics calculations and nuclear magnetic resonance-driven docking computations showing two binding sites for plant cytochrome c at the head soluble domain of plant cytochrome c1, namely a non-productive (or distal) site with a long heme-to-heme distance and a functional (or proximal) site with the two heme groups close enough as to allow electron transfer. As inferred from isothermal titration calorimetry experiments, the two binding sites exhibit different equilibrium dissociation constants, for both reduced and oxidized species, that are all within the micromolar range, thus revealing the transient nature of such a respiratory complex. Although the docking of cytochrome c at the distal site occurs at the interface between cytochrome c1 and the Rieske subunit, it is fully compatible with the complex III structure. In our model, the extra distal site in complex III could indeed facilitate the functional cytochrome c channeling towards complex IV by building a "floating boat bridge" of cytochrome c molecules (between complexes III and IV) in plant respirasome. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Cytochrome cbb3 of Thioalkalivibrio is a Na+-pumping cytochrome oxidase

    Muntyan, M.S.; Cherepanov, D.A.; Malinen, A.M.; Bloch, D.A.; Sorokin, D.Y.; Severina, I.I.; Ivashina, T.V.; Lahti, R.; Muyzer, G.; Skulachev, V.P.

    2015-01-01

    Cytochrome c oxidases (Coxs) are the basic energy transducers in the respiratory chain of the majority of aerobic organisms. Coxs studied to date are redox-driven proton-pumping enzymes belonging to one of three subfamilies: A-, B-, and C-type oxidases. The C-type oxidases (cbb3 cytochromes), which

  11. Effect of ethylene glycol monomethyl ether and diethylene glycol monomethyl ether on hepatic metabolizing enzymes.

    Kawamoto, T; Matsuno, K; Kayama, F; Hirai, M; Arashidani, K; Yoshikawa, M; Kodama, Y

    1990-06-01

    Glycol ethers have been extensively used in industry over the past 40-50 years. Numerous studies on the toxicity of glycol ethers have been performed, however, the effects of glycol ethers on the hepatic drug metabolizing enzymes are still unknown. We studied the changes of the putative metabolic enzymes, that is, the hepatic microsomal mixed function oxidase system and cytosolic alcohol dehydrogenase, by the oral administration of diEGME and EGME. Adult male Wistar rats were used. DiEGME was administered orally; 500, 1000, 2000 mg/kg for 1, 2, 5 or 20 days and EGME was 100, 300 mg/kg for 1, 2, 5 or 20 days. Decreases in liver weights were produced by highest doses of diEGME (2000 mg/kg body wt/day for 20 days) and EGME (300 mg/kg body wt/day for 20 days). DiEGME increased hepatic microsomal protein contents and induced cytochrome P-450, but not cytochrome b5 or NADPH-cytochrome c reductase. The activity of cytosolic ADH was not affected by diEGME administration. On the other hand, EGME did not change cytochrome P-450, cytochrome b5 or NADPH-cytochrome c reductase. The activity of cytosolic ADH was increased by repeated EGME treatment. Therefore it is suspected that the enzyme which takes part in the metabolism of diEGME is different from that of EGME, although diEGME is a structural homologue of EGME.

  12. Hepatitis B Foundation

    ... worldwide 2 Billion People have been infected with Hepatitis B Worldwide The Hepatitis B Foundation is working ... of people living with hepatitis B. Learn About Hepatitis B in 11 Other Languages . Resource Video See ...

  13. What Is Hepatitis?

    ... Navigation Alt+1 Content Alt+2 What is hepatitis? Online Q&A Reviewed July 2016 Q: What ... Question and answer archives Submit a question World Hepatitis Day Posters: Eliminate hepatitis World Hepatitis Day 2017 ...

  14. Feature Hepatitis: Hepatitis Symptoms, Diagnosis, Treatment & Prevention

    ... Navigation Bar Home Current Issue Past Issues Feature Hepatitis Hepatitis: Symptoms, Diagnosis, Treatment & Prevention Past Issues / Spring 2009 ... No appetite Fever Headaches Diagnosis To check for hepatitis viruses, your doctor will test your blood. You ...

  15. Liver Cancer and Hepatitis B

    ... Clinical Trials Physician Directory HBV Meeting What Is Hepatitis B? What Is Hepatitis B? The ABCs of Viral Hepatitis Liver Cancer and Hepatitis B Hepatitis Delta Coinfection Hepatitis C Coinfection HIV/AIDS ...

  16. Hepatitis C: Sex and Sexuality

    ... with Hepatitis » Sex and Sexuality: Entire Lesson Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... hepatitis C virus through sex. Can you pass hepatitis C to a sex partner? Yes, but it ...

  17. Hepatitis C: Diet and Nutrition

    ... with Hepatitis » Daily Living: Diet and Nutrition Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... have high cholesterol and have fatty liver. How hepatitis C affects diet If you have hepatitis, you ...

  18. Hepatitis B & C and HIV

    ... Find Services HIV SERVICES LOCATOR Locator Search Search Hepatitis B & C Topics Hepatitis B Hepatitis C Hepatitis ... Infections Sexually Transmitted Diseases Smoking Women's Health Issues Hepatitis B Virus and Hepatitis C Virus Infection People ...

  19. [Autoimmune hepatitis].

    Färkkilä, Martti

    2013-01-01

    Autoimmune hepatitis is chronic liver disease with two subtypes, type 1 with anti nuclear or smooth muscle antibodies and type 2 with LKM1 or LC1 antibodies, and both with hypergammaglobulinemia and typical histology. Prevalence of AIH is between 10 to 17 per 100000 in Europe. Up to 20-40 % of cases present with acute hepatitis. Budesonide can be used as a first line induction therapy in non-cirrhotic patients, and tiopurines, mercaptopurine or mycophenolic acid as maintenance therapies. Patients not responding to conventional therapy can be treated with ciclosporin, tacrolimus or rituximab or finally with liver transplantation.

  20. Regulation of cytochrome P-450 monooxygenases in the mouse

    Kelley, M.F.

    1986-01-01

    Recently, the compound 1,4-bis[2-(3,4-dichloropyridyloxy)] benzene (TCPOBOP) has been identified as a highly potent phenobabital-like agonist in mice. This finding has led to the suggestion that a receptor-mediated process may govern the induction of cytochrome P-450 monooxygenases by phenobarbital and phenobarbital-like agonists. This dissertation examines: (1) the effects of structural alterations of the TCPOBOP molecule on enzyme induction activity, (2) the induction response to phenobarbital and TCPOBOP among inbred mouse strains, (3) the spectrum of monooxygenase activities induced by phenobarbital and TCPOBOP compared to 3-methylcholanthrene, isosafrole and pregnenolone 16α-carbonitrile (PCN) and (4) the binding of [ 3 H] TCPOBOP in hepatic cytosol. Changes in the structure of the pyridyloxy or benzene rings markedly affect enzyme induction activity and provide additional indirect evidence for a receptor-mediated response. An evaluation of monooxygenase induction by TCPOBOP for 27 inbred mouse strains and by phenobarbital for 15 inbred mouse strains failed to identify a strain which was completely nonresponsive to these compounds, although several strains exhibited decreased responsiveness for select monooxygenase reactions. TCPOBOP, PCN and phenobarbital were all found to significantly increase the rate of hydroxylation of testosterone at the 2α-, 6β- and 15β- positions but only TCPOBOP and phenobarbital dramatically increased the rate of pentoxyresorufin O-dealkylation. The results demonstrates that TCPOBOP most closely resembles phenobarbital in its mode of monooxygenase induction in mice. Sucrose density gradient analysis of [ 3 H] TCPOBOP-hepatic cytosol incubations failed to identify specific, saturable binding of [ 3 H] TCPOBOP to cytosolic marcomolecular elements

  1. Hepatitis E

    ... room/fact-sheets/detail/hepatitis-e","@context":"http://schema.org","@type":"Article"}; العربية 中文 français русский español ... E: recognition, investigation and control”. The manual gives information about the epidemiology, clinical manifestations of the disease, ...

  2. Hepatic haemangioma

    Hp 630 Dual Core

    successful usage of transhepatic compression sutures using polytetrafluoroethylene (PTFE) pledgets and selective ligation of large feeding vessels from right hepatic artery. Surgical resection may not be technically safe or possible in certain cases due to the massive or diffuse nature of the lesion, proximity to vascular ...

  3. Hepatitis B

    ... which can lower your chances of developing serious health problems. Your doctor may recommend screening for hepatitis B if you ... see a doctor who specializes in liver diseases. Doctors can treat the health problems related to cirrhosis with medicines, surgery, and other ...

  4. Chronic hepatitis

    infection by four diagnostic systems: first generation and second generation. ELlSA, second generation recombinant immunoblot assay and nested polymerase chain reaction analysis. HepatoJogy 1992; 16: 300-305. 14. Van der Poel CL, ... Alpha-1-antitrypsin deficiency. Alcoholic hepatitis. Non-alcoholic steatohepatitis.

  5. Radiogenic hepatitis

    Rey, G; Woellgens, P; Haase, W [Katharinenhospital, Stuttgart (F.R. Germany). Strahlenklinik

    1976-08-01

    The article is about a patient who developed hepatitis after post-operative radiotherapy of a hypernephroma on the right side with /sup 60/Co ..gamma.. radiation. The scintigraph showed a normal-sized liver with parenchymal defects. Therapy consisted of anti-emetics and vitamin preparations.

  6. Hepatic Encephalopathy

    Full Text Available ... Lipase Deficiency Liver Cancer Liver Cysts Non-Alcoholic Fatty Liver Disease Primary Biliary Cholangitis Primary Sclerosing Cholangitis What ... B & C Alcohol-related Liver Disease Non-alcoholic Fatty Liver Disease (NAFLD) & Non-alcoholic Steatohepatitis (NASH) Autoimmune Hepatitis ...

  7. Hepatic Encephalopathy

    Full Text Available ... of brain function in people with advanced liver disease. When your liver is damaged it can no longer remove toxic substances from your blood. These toxins build up and can travel through your body until they reach your brain, causing mental and physical symptoms of HE. Hepatic Encephalopathy often ...

  8. Hepatic Encephalopathy

    Full Text Available ... damages your liver over many years – such as long-term alcohol abuse or chronic hepatitis – can cause ... treated. It’s important to continue treatment for as long as necessary to keep HE from coming back. ...

  9. Genetic defects of cytochrome c oxidase assembly

    Pecina, Petr; Houšťková, H.; Hansíková, H.; Zeman, J.; Houštěk, Josef

    2004-01-01

    Roč. 53, Suppl. 1 (2004), s. S213-S223 ISSN 0862-8408 R&D Projects: GA ČR GA303/03/0749 Institutional research plan: CEZ:AV0Z5011922 Keywords : cytochrome c oxidase * mitochondrial disorders Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 1.140, year: 2004

  10. Hepatic amebiasis

    Salles José Maria

    2003-01-01

    Full Text Available Amebiasis can be considered the most aggressive disease of the human intestine, responsible in its invasive form for clinical syndromes, ranging from the classic dysentery of acute colitis to extra-intestinal disease, with emphasis on hepatic amebiasis, unsuitably named amebic liver abscess. Found worldwide, with a high incidence in India, tropical regions of Africa, Mexico and other areas of Central America, it has been frequently reported in Amazonia. The trophozoite reaches the liver through the portal system, provoking enzymatic focal necrosis of hepatocytes and multiple micro-abscesses that coalesce to develop a single lesion whose central cavity contains a homogeneous thick liquid, with typically reddish brown and yellow color similar to "anchovy paste". Right upper quadrant pain, fever and hepatomegaly are the predominant symptoms of hepatic amebiasis. Jaundice is reported in cases with multiple lesions or a very large abscess, and it affects the prognosis adversely. Besides chest radiography, ultrasonography and computerized tomography have brought remarkable contributions to the diagnosis of hepatic abscesses. The conclusive diagnosis is made however by the finding of Entamoeba histolytica trophozoites in the pus and by the detection of serum antibodies to the amoeba. During the evolution of hepatic amebiasis, in spite of the availability of highly effective drugs, some important complications may occur with regularity and are a result of local perforation with extension into the pleural and pericardium cavities, causing pulmonary abscesses and purulent pericarditis, respectively The ruptures into the abdominal cavity may lead to subphrenic abscesses and peritonitis. The treatment of hepatic amebiasis is made by medical therapy, with metronidazole as the initial drug, followed by a luminal amebicide. In patients with large abscesses, showing signs of imminent rupture, and especially those who do not respond to medical treatment, a

  11. Hepatic amebiasis

    José Maria Salles

    Full Text Available Amebiasis can be considered the most aggressive disease of the human intestine, responsible in its invasive form for clinical syndromes, ranging from the classic dysentery of acute colitis to extra-intestinal disease, with emphasis on hepatic amebiasis, unsuitably named amebic liver abscess. Found worldwide, with a high incidence in India, tropical regions of Africa, Mexico and other areas of Central America, it has been frequently reported in Amazonia. The trophozoite reaches the liver through the portal system, provoking enzymatic focal necrosis of hepatocytes and multiple micro-abscesses that coalesce to develop a single lesion whose central cavity contains a homogeneous thick liquid, with typically reddish brown and yellow color similar to "anchovy paste". Right upper quadrant pain, fever and hepatomegaly are the predominant symptoms of hepatic amebiasis. Jaundice is reported in cases with multiple lesions or a very large abscess, and it affects the prognosis adversely. Besides chest radiography, ultrasonography and computerized tomography have brought remarkable contributions to the diagnosis of hepatic abscesses. The conclusive diagnosis is made however by the finding of Entamoeba histolytica trophozoites in the pus and by the detection of serum antibodies to the amoeba. During the evolution of hepatic amebiasis, in spite of the availability of highly effective drugs, some important complications may occur with regularity and are a result of local perforation with extension into the pleural and pericardium cavities, causing pulmonary abscesses and purulent pericarditis, respectively The ruptures into the abdominal cavity may lead to subphrenic abscesses and peritonitis. The treatment of hepatic amebiasis is made by medical therapy, with metronidazole as the initial drug, followed by a luminal amebicide. In patients with large abscesses, showing signs of imminent rupture, and especially those who do not respond to medical treatment, a

  12. Spaceflight Effects on Cytochrome P450 Content in Mouse Liver.

    Natalia Moskaleva

    Full Text Available Hard conditions of long-term manned spaceflight can affect functions of many biological systems including a system of drug metabolism. The cytochrome P450 (CYP superfamily plays a key role in the drug metabolism. In this study we examined the hepatic content of some P450 isoforms in mice exposed to 30 days of space flight and microgravity. The CYP content was established by the mass-spectrometric method of selected reaction monitoring (SRM. Significant changes in the CYP2C29, CYP2E1 and CYP1A2 contents were detected in mice of the flight group compared to the ground control group. Within seven days after landing and corresponding recovery period changes in the content of CYP2C29 and CYP1A2 returned to the control level, while the CYP2E1 level remained elevated. The induction of enzyme observed in the mice in the conditions of the spaceflight could lead to an accelerated biotransformation and change in efficiency of pharmacological agents, metabolizing by corresponding CYP isoforms. Such possibility of an individual pharmacological response to medication during long-term spaceflights and early period of postflight adaptation should be taken into account in space medicine.

  13. Comparison of basal and induced cytochromes P450 in 6 species of waterfowl

    Melancon, M.J.; Rattner, B.A.; Hoffman, D.J.; Beeman, D.; Day, D.; Custer, T.

    1999-01-01

    Cytochrome P450-associated monooxygenase activities were measured in control and prototype inducer-treated mallard duck, black duck, wood duck, lesser scaup, Canada goose and mute swan. Ages of the birds ranged from pipping embryos (that were treated approximately 3 days before pipping) to adults. Three or more of the following hepatic microsomal monooxygenases were assayed in each species: Benzyloxyresorufin-O-dealkylase (BROD), Ethoxyresorufin-O-dealkylase (EROD), methoxyresorufin-O-dealkylase (MROD), and pentoxyresorufin-O-dealkylase (PROD). Baseline activities differed between species, but because of differences in ages, sources of the eggs or birds, and diets, these cannot be viewed as absolute differences. The cytochrome P450 inducers utilized were beta-naphthoflavone (BNF), 3-methylcholanthrene (3MC) and phenobarbital (PB). In general, there was little response to PB; only lesser scaup were induced to greater than three times control level and most species were well under this. Responses to BNF and 3MC occurred in each species studied, but differed in which of the monooxygenases was most induced (absolute values and ratios to control values) and in relative induction between species. BROD frequently had an induction ratio EROD. Overall, lesser scaup were the most responsive, canada geese the least responsive, and the other species intermediate in responsiveness to the cytochrome P450 inducers studied.

  14. Counter-attack on viral hepatitis. [Hepatitis A; Hepatitis B

    Prozesky, O W [Pretoria Univ. (South Africa). Dept. of Medical Virology; Jupp, P G; Joubert, J J; Taylor, M B; Grabow, W O.K.

    1985-07-01

    The most highly developed radioimmunoassay test system in medical virology is proving of exceptional value in research aimed at controlling and eventually eradicating the scourge of human hepatitis. The use of radioimmunoassay in detecting hepatitis A (HAV) and hepatitis B (HBV) viruses is discussed. The hepatitis A virus is an enterovirus which infects the gastrointestinal tract and is usually transmitted by contaminated food, milk or water. Hepatitis B spreads mainly by the parenteral rate. Bedbugs and ticks are considered as possible transmitters of HBV. Another important contribution of radioimmunoassay is the ability to monitor the immune response of persons at risk who are vaccinated against hepatitis B.

  15. Hepatitis B (HBV)

    ... Staying Safe Videos for Educators Search English Español Hepatitis B KidsHealth / For Teens / Hepatitis B What's in ... Prevented? Print en español Hepatitis B What Is Hepatitis B? Hepatitis B is an infection of the ...

  16. Hepatitis A Vaccine

    Twinrix® (as a combination product containing Hepatitis A Vaccine, Hepatitis B Vaccine) ... Why get vaccinated against hepatitis A?Hepatitis A is a serious liver disease. It is caused by the hepatitis A virus (HAV). HAV is spread from ...

  17. AUTOIMMUNE HEPATITIS

    Yusri Dianne Jurnalis

    2010-05-01

    Full Text Available AbstrakHepatitis autoimun merupakan penyakit inflamasi hati yang berat dengan penyebab pasti yang tidak diketahui yang mengakibatkan morbiditas dan mortalitas yang tinggi. Semua usia dan jenis kelamin dapat dikenai dengan insiden tertinggi pada anak perempuan usia prepubertas, meskipun dapat didiagnosis pada usia 6 bulan. Hepatitis autoimun dapat diklasifikasikan menjadi 2 bagian berdasarkan adanya antibodi spesifik: Smooth Muscle Antibody (SMA dengan anti-actin specificity dan/atau Anti Nuclear Antibody (ANA pada tipe 1 dan Liver-Kidney Microsome antibody (LKM1 dan/atau anti-liver cytosol pada tipe 2. Gambaran histologisnya berupa “interface hepatitis”, dengan infiltrasi sel mononuklear pada saluran portal, berbagai tingkat nekrosis, dan fibrosis yang progresf. Penyakit berjalan secara kronik tetapi keadaan yang berat biasanya menjadi sirosis dan gagal hati.Tipe onset yang paling sering sama dengan hepatitis virus akut dengan gagal hati akut pada beberapa pasien; sekitar sepertiga pasien dengan onset tersembunyi dengan kelemahan dan ikterik progresif ketika 10-15% asimptomatik dan mendadak ditemukan hepatomegali dan/atau peningkatan kadar aminotransferase serum. Adanya predominasi perempuan pada kedua tipe. Pasien LKM1 positif menunjukkan keadaan lebih akut, pada usia yang lebih muda, dan biasanya dengan defisiensi Immunoglobulin A (IgA, dengan durasi gejala sebelum diagnosis, tanda klinis, riwayat penyakit autoimun pada keluarga, adanya kaitan dengan gangguan autoimun, respon pengobatan dan prognosis jangka panjang sama pada kedua tipe.Kortikosteroid yang digunakan secara tunggal atau kombinasi azathioprine merupakan terapi pilihan yang dapat menimbulkan remisi pada lebih dari 90% kasus. Strategi terapi alternatif adalah cyclosporine. Penurunan imunosupresi dikaitkan dengan tingginya relap. Transplantasi hati dianjurkan pada penyakit hati dekom-pensata yang tidak respon dengan pengobatan medis lainnya.Kata kunci : hepatitis Autoimmune

  18. Autoimmune hepatitis.

    Vergani, D; Mieli-Vergani, G

    2004-06-01

    Autoimmune hepatitis (AIH) is characterised histologically by interface hepatitis, and serologically by the presence of non-organ and liver specific autoantibodies and increased levels of immunoglobulin G. Its onset is often ill-defined, frequently mimicing acute hepatitis. AIH usually responds to immunosuppressive treatment, which should be instituted as soon as diagnosis is made. Two types of AIH are recognized according to seropositivity for smooth muscle and/or antinuclear antibody (SMA/ANA, type 1 AIH) or liver kidney microsomal type 1 antibody (LKM1, type 2 AIH). There is a female predominance in both. LKM1 positive patients tend to present more acutely, at a younger age and commonly have immunoglobulin A deficiency, while duration of symptoms before diagnosis, clinical signs, family history of autoimmunity, presence of associated autoimmune disorders, response to treatment and long-term prognosis are similar in the 2 groups. Susceptibility to AIH type 1 is conferred by possession of HLA DR3 and DR4, while to AIH type 2 by possession of HLA DR7. Liver damage is likely to derive from an immune reaction to liver cell antigens, possibly triggered by a mechanism of molecular mimicry, where immune responses to external pathogens, e.g. viruses, become directed towards structurally similar self-components. In AIH this process would be perpetuated by impairment in immune regulation.

  19. Hepatic (Liver) Function Panel

    ... Educators Search English Español Blood Test: Hepatic (Liver) Function Panel KidsHealth / For Parents / Blood Test: Hepatic (Liver) ... kidneys ) is working. What Is a Hepatic (Liver) Function Panel? A liver function panel is a blood ...

  20. Hepatitis C and Incarceration

    ... Hepatitis Cdo to take care of their liver? People with Hepatitis C should not use alcohol or street drugs, as these can hurt the liver. Some other products can also hurt people with Hepatitis C, even if they appear to ...

  1. Hepatitis B virus (image)

    Hepatitis B is also known as serum hepatitis and is spread through blood and sexual contact. It is ... population. This photograph is an electronmicroscopic image of hepatitis B virus particles. (Image courtesy of the Centers for ...

  2. Hepatitis Risk Assessment

    ... please visit this page: About CDC.gov . Hepatitis Risk Assessment Recommend on Facebook Tweet Share Compartir Viral Hepatitis. Are you at risk? Take this 5 minute Hepatitis Risk Assessment developed ...

  3. Effect of fumonisin B1 on rat hepatic P450 system

    Spotti, M.; Maas, R.F.M.; Nijs, C.M. de; Fink-Gremmels, J.

    2000-01-01

    The effects of the mycotoxin fumonisin B1 (FB1) on the hepatic cytochrome P450 system were investigated in male rats dosed daily by oral gavage with 3 mg FB1 per kg body weight for 9 consecutive days. FB1 treatment resulted in a reduced weight gain. At the same time, CYP2E activity was increased,

  4. Relation among cytochrome P450, AH-active PCB congeners and dioxin equivalents in pipping black-crowned night-heron embryos

    Rattner, B.A.; Hatfield, J.S.; Melancon, M.J.; Custer, T.W.; Tillitt, D.E.

    1994-01-01

    Pipping black-crowned night-heron (Nycticorax nycticorax) embryos were collected from a relatively uncontaminated site (next to Chincoteague National Wildlife Refuge, VA) and three polluted sites (Cat Island, Green Bay, Lake Michigan, WI; Bair Island, San Francisco Bay, CA; West Marin Island, San Francisco Bay, CA). Hepatic cytochrome P-450-associated monooxygenases and cytochrome P-450 proteins, induced up to 85-fold relative to the reference site, were associated with concentrations of total polychlorinated biphenyls (PCBs) and 11 PCB congeners that are presumed to express toxicity through the arylhydrocarbon (Ah) receptor. Multiple regression revealed that up to 86% of the variation of cytochrome P450 measurements was accounted for by variation in the concentration of these PCB congeners. Toxic equivalents (TEQs) of sample extracts, predicted mathematically (summed product of PCB congener concentrations and toxic equivalency factors), and dioxin equivalents (TCDD-EQs), derived by bioassay (ethoxyresorufin-O-dealkylase activity of treated H4IIE rat hepatoma cells), were greatest in Cat Island samples. Cytochrome P450-associated monooxygenases and cytochrome P450 proteins were related to TEQs and TCDD-EQs; adjusted r-2 often exceeded 0.5 for the relation among mathematically predicted TEQs and cytochrome P450 measurements. These data extend previous observations in heron embryos of an association between P450 and total PCB burdens to include Ah-active PCB congeners, and presumably other compounds, which interact similarly with the Ah receptor. Benzyloxyresorufin O-dealkylase, ethoxyresorufin O-dealkylase, and cytochrome P450 1A appear to be the most reliable measures of exposure to Ah-active PCB congeners in black-crowned night-heron embryos. These findings provide further evidence that cytochrome P450-associated parameters have considerable value as a biomarker for assessing environmental contamination of wetlands.

  5. Hepatitis B Vaccine

    ... a combination product containing Haemophilus influenzae type b, Hepatitis B Vaccine) ... combination product containing Diphtheria, Tetanus Toxoids, Acellular Pertussis, Hepatitis B, Polio Vaccine)

  6. Fluconazole is a potent inhibitor of antipyrine metabolism in vivo in mice

    La Delfa, I.; Zhu, Q.M.; Mo, Z.; Blaschke, T.F.

    1989-01-01

    Fluconazole, a bis-triazole antifungal, is distinguished from imidazole antifungals (e.g. ketoconazole) by its potency and pharmacokinetic characteristics. Imidazole-containing compounds are well documented to inhibit the hepatic cytochrome P-450-dependent enzyme system; whether this effect occurs with a bis-triazole agent is unknown. The (/sup 14/C)antipyrine breath test was employed to investigate the effects of fluconazole on this enzyme system in CD-1 male mice. Control, ketoconazole (100 mg/kg), and fluconazole (1 and 10 mg/kg) were studied in single- and multiple-dose experiments. Fluconazole had potent inhibitory effects on the total (mean = -73% +/- 2%), demethylase (mean = -90% +/- 2%), and nondemethylase (mean = -60% +/- 4%) elimination rate constants (all p less than 0.001). The fraction of the administered radioactivity excreted as /sup 14/CO/sub 2/ was decreased by 50-80% in the fluconazole groups (p less than 0.001). These effects were seen after single- and multiple-dose studies; however, return to baseline occurred more quickly in the multiple-dose group. These effects were significantly more pronounced than those observed with equipotent doses of ketoconazole. These results provide evidence that fluconazole is a potent, partially selective, and reversible inhibitor of the cytochrome P-450-dependent enzyme system in mice. Future studies will be required to assess this property and possible interactions with drugs metabolized by this enzyme system in humans.

  7. INDUCTION AND SUPPRESSION OF CYTOCHROME P450 1A BY 3,3', 4,4', 5-PENTACHLOROBIPHENYL AND ITS RELATIONSHIP TO OXIDATIVE STRESS IN THE MARINE FISH SCUP (STENOTOMUS CHRYSOPS). (R827102)

    AbstractThe planar polychlorinated biphenyl (PCB) 3,3',4,4'-tetrachlorobiphenyl (TCB) causes dose-dependent induction and post-transcriptional suppression of hepatic cytochrome P450 1A (CYP1A) in the marine teleost scup (Stenotomus chrysops). That suppr...

  8. Altered carbohydrate, lipid, and xenobiotic metabolism by liver from rats flown on Cosmos 1887

    Merrill, A. H. Jr; Hoel, M.; Wang, E.; Mullins, R. E.; Hargrove, J. L.; Jones, D. P.; Popova, I. A.; Merrill AH, J. r. (Principal Investigator)

    1990-01-01

    To determine the possible biochemical effects of prolonged weightlessness on liver function, samples of liver from rats that had flown aboard Cosmos 1887 were analyzed for protein, glycogen, and lipids as well as the activities of a number of key enzymes involved in metabolism of these compounds and xenobiotics. Among the parameters measured, the major differences were elevations in the glycogen content and hydroxymethylglutaryl-CoA (HMG-CoA) reductase activities for the rats flown on Cosmos 1887 and decreases in the amount of microsomal cytochrome P-450 and the activities of aniline hydroxylase and ethylmorphine N-demethylase, cytochrome P-450-dependent enzymes. These results support the earlier finding of differences in these parameters and suggest that altered hepatic function could be important during spaceflight and/or the postflight recovery period.

  9. The reaction of neuroglobin with potential redox protein partners cytochrome b5  and cytochrome c

    Fago, Angela; Mathews, A.J.; Moens, L.

    2006-01-01

    Previously identified, potentially neuroprotective reactions of neuroglobin require the existence of yet unknown redox partners. We show here that the reduction of ferric neuroglobin by cytochrome b5 is relatively slow (k=6×102M-1s-1 at pH 7.0) and thus is unlikely to be of physiological...... significance. In contrast, the reaction between ferrous neuroglobin and ferric cytochrome c is very rapid (k=2×107M-1s-1) with an apparent overall equilibrium constant of 1μM. Based on this data we propose that ferrous neuroglobin may well play a role in preventing apoptosis...

  10. Soybean meal fermented by Aspergillus awamori increases the cytochrome P-450 content of the liver microsomes of mice.

    Kishida, T; Ataki, H; Takebe, M; Ebihara, K

    2000-04-01

    The effect of soybean meal fermented by Aspergillus awamori on the acute lethality of acetaldehyde, pentobarbital sleeping time, and cytochrome P-450 content of the hepatic microsomes was studied in mice. Most of the daidzin and genistin in soybean meal (SBM) were converted into the respective aglycones, daidzein and genistein, by fermentation. In experiment 1, mice were fed isonitrogenic test diets with one of the following five protein sources for 28 d: casein, SBM, fermented and hot-air-dried SBM (FSBM-HD), fermented and freeze-dried SBM (FSBM-FD), or methanol-extracted FSBM-FD (FSMB-FD-R). The acute lethality of acetaldehyde in mice fed the FSBM-FD diet was significantly lower than that in mice fed the SBM, FSBM-HD, or FSBM-FD-R diet. In experiments 2 and 3, mice were fed isonitrogenic test diets with one of the following four protein sources for 28 d: casein, SBM, FSBM-FD, and FSBM-FD-R. The pentobarbital sleeping time was significantly shorter and the cytochrome P-450 content was significantly higher in the mice fed the FSBM-FD diet than the respective value in mice fed the other test diets. In experiment 4, mice were fed one of eight diets which contained different levels of aglycone obtained by varying the proportion of FSBM-FD and FSBM-FD-R, for 28 d. The cytochrome P-450 content in hepatic microsomes increased as the dietary level of isoflavonoid aglycones increased, but there was a saturation phenomenon. These results suggest that soy isoflavonoid aglycones are more potent inducers of cytochrome P-450 than isoflavonoid glycosides.

  11. HIV and Viral Hepatitis

    ... common causes of viral hepatitis are hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV). HBV and HCV are common ... gov/ mmwr/ preview/ mmwrhtml/ rr5516a1. htm? s_ cid= rr5516a1_ e. The Numbers • • Of people with HIV in the ...

  12. New insight into the mechanism of mitochondrial cytochrome c function

    Chertkova, Rita V; Brazhe, Nadezda A; Bryantseva, Tatiana V

    2017-01-01

    We investigate functional role of the P76GTKMIFA83 fragment of the primary structure of cytochrome c. Based on the data obtained by the analysis of informational structure (ANIS), we propose a model of functioning of cytochrome c. According to this model, conformational rearrangements of the P76...... with conformational changes and reduced mobility of heme porphyrin. This points to a significant role of the P76GTKMIFA83 fragment in the electron transport function of cytochrome c....

  13. Cytochrome P450 monooxygenases and insecticide resistance in insects.

    Bergé, J B; Feyereisen, R; Amichot, M

    1998-01-01

    Cytochrome P450 monooxygenases are involved in many cases of resistance of insects to insecticides. Resistance has long been associated with an increase in monooxygenase activities and with an increase in cytochrome P450 content. However, this increase does not always account for all of the resistance. In Drosophila melanogaster, we have shown that the overproduction of cytochrome P450 can be lost by the fly without a corresponding complete loss of resistance. These results prompted the seque...

  14. Genetic polymorphism of human cytochrome P-450 (S)-mephenytoin 4-hydroxylase. Studies with human autoantibodies suggest a functionally altered cytochrome P-450 isozyme as cause of the genetic deficiency

    Meier, U.T.; Meyer, U.A.

    1987-01-01

    The metabolism of the anticonvulsant mephenytoin is subject to a genetic polymorphism. In 2-5% of Caucasians and 18-23% of Japanese subjects a specific cytochrome P-450 isozyme, P-450 meph, is functionally deficient or missing. The authors have accumulated evidence that autoimmune antibodies observed in sera of patients with tienilic acid induced hepatitis (anti-liver kidney microsome 2 or anti-LKM2 antibodies) specifically recognize the cytochrome P-450 involved in the mephrenytoin hydroxylation polymorphism. This is demonstrated by immunoinhibition and immunoprecipitation of microsomal (S)-mephenytoin 4-hydroxylation activity and by the recognition by anti-LKM2 antibodies of a single [ 125 I]-protein band on immunoblots of human liver microsomes after sodium dodecyl sulfate-polyacrylamide gel electrophoresis or isoelectric focusing. The cytochrome P-450 recognized by anti-LKM2 antibodies was immunopurified from microsomes derived from livers of extensive (EM) or poor metabolizers (PM) of (S)-mephenytoin. Comparison of the EM-type cytochrome P-450 to that isolated from PM livers revealed no difference in regard to immuno-cross-reactivity, molecular weight, isoelectric point, relative content in microsomes, two-dimensional tryptic peptide maps, one-dimensional peptide maps with three proteases, amino acid composition, and amino-terminal protein sequence. Finally, the same protein was precipitated from microsomes prepared from the liver biopsy of a subject phenotyped in vivo as a poor metabolizer of mephenytoin. These data strongly suggest that the mephenytoin hydroxylation deficiency is caused by a minor structural change leading to a functionally altered cytochrome P-450 isozyme

  15. Prediction of cytochrome P450 mediated metabolism

    Olsen, Lars; Oostenbrink, Chris; Jørgensen, Flemming Steen

    2015-01-01

    Cytochrome P450 enzymes (CYPs) form one of the most important enzyme families involved in the metabolism of xenobiotics. CYPs comprise many isoforms, which catalyze a wide variety of reactions, and potentially, a large number of different metabolites can be formed. However, it is often hard...... to rationalize what metabolites these enzymes generate. In recent years, many different in silico approaches have been developed to predict binding or regioselective product formation for the different CYP isoforms. These comprise ligand-based methods that are trained on experimental CYP data and structure...

  16. CYTOCHROME P450 REGULATION: THE INTERPLAY BETWEEN ITS HEME AND APOPROTEIN MOIETIES IN SYNTHESIS, ASSEMBLY, REPAIR AND DISPOSAL123

    Correia, Maria Almira; Sinclair, Peter R.; De Matteis, Francesco

    2010-01-01

    Heme is vital to our aerobic universe. Heme cellular content is finely tuned through an exquisite control of synthesis and degradation. Heme deficiency is deleterious to cells, whereas excess heme is toxic. Most of the cellular heme serves as the prosthetic moiety of functionally diverse hemoproteins, including cytochromes P450 (P450s). In the liver, P450s are its major consumers with >50% of hepatic heme committed to their synthesis. Prosthetic heme is the sine qua non of P450 catalytic biot...

  17. LKM-1 autoantibodies recognize a short linear sequence in P450IID6, a cytochrome P-450 monooxygenase.

    Manns, M P; Griffin, K J; Sullivan, K F; Johnson, E F

    1991-01-01

    LKM-1 autoantibodies, which are associated with autoimmune chronic active hepatitis, recognize P450IID6, a cytochrome P-450 monooxygenase. The reactivities of 26 LKM-1 antisera were tested with a panel of deletion mutants of P450IID6 expressed in Escherichia coli. 22 sera recognize a 33-amino acid segment of P450IID6, and 11 of these recognize a shorter segment, DPAQPPRD. PAQPPR is also found in IE175 of herpes simplex virus type 1 (HSV-1). Antibodies for HSV-1 proteins were detected by ELISA...

  18. Hepatic radiography

    Bernardino, M.E.; Sones, P.J.

    1985-01-01

    The past several years have seen significant advances in diagnostic and interventional radiology. These advances have been particularly rewarding for the study of liver disease. Improved imaging and therapeutic procedures in oncology have generated changes in treatment protocols and in evaluating the results of therapy for hepatic malignancies. The enriched understanding of the anatomic and hemodynamic aspects of the portal system has greatly benefited patients with portal hypertension. Now physicians are confidently more aggressive in the therapeutic approach to the variceal bleeder, and they have modified their approach to the preservation of portal flow following shunt. All of the diagnostic modalities used to evaluate the liver are represented in this book. In its structure and organization this volume goes beyond a historical overview of imaging to present greater insight into the current state of the art, as well as possible future developments. Each chapter is designed to elucidate the advantages and weaknesses of the various diagnostic modalities

  19. Cytochrome b5 and epoxide hydrolase contribute to benzo[a]pyrene-DNA adduct formation catalyzed by cytochrome P450 1A1 under low NADPH:P450 oxidoreductase conditions

    Stiborová, Marie; Moserová, Michaela; Černá, Věra; Indra, Radek; Dračínský, Martin; Šulc, Miroslav; Henderson, Colin J.; Wolf, C. Roland; Schmeiser, Heinz H.; Phillips, David H.; Frei, Eva; Arlt, Volker M.

    2014-01-01

    In previous studies we had administered benzo[a]pyrene (BaP) to genetically engineered mice (HRN) which do not express NADPH:cytochrome P450 oxidoreductase (POR) in hepatocytes and observed higher DNA adduct levels in livers of these mice than in wild-type mice. To elucidate the reason for this unexpected finding we have used two different settings for in vitro incubations; hepatic microsomes from control and BaP-pretreated HRN mice and reconstituted systems with cytochrome P450 1A1 (CYP1A1), POR, cytochrome b 5 , and epoxide hydrolase (mEH) in different ratios. In microsomes from BaP-pretreated mice, in which Cyp1a1 was induced, higher levels of BaP metabolites were formed, mainly of BaP-7,8-dihydrodiol. At a low POR:CYP1A1 ratio of 0.05:1 in the reconstituted system, the amounts of BaP diones and BaP-9-ol formed were essentially the same as at an equimolar ratio, but formation of BaP-3-ol was ∼1.6-fold higher. Only after addition of mEH were BaP dihydrodiols found. Two BaP-DNA adducts were formed in the presence of mEH, but only one when CYP1A1 and POR were present alone. At a ratio of POR:CYP1A1 of 0.05:1, addition of cytochrome b 5 increased CYP1A1-mediated BaP oxidation to most of its metabolites indicating that cytochrome b 5 participates in the electron transfer from NADPH to CYP1A1 required for enzyme activity of this CYP. BaP-9-ol was formed even by CYP1A1 reconstituted with cytochrome b 5 without POR. Our results suggest that in livers of HRN mice Cyp1a1, cytochrome b 5 and mEH can effectively activate BaP to DNA binding species, even in the presence of very low amounts of POR

  20. The SMARTCyp cytochrome P450 metabolism prediction server

    Rydberg, Patrik; Gloriam, David Erik Immanuel; Olsen, Lars

    2010-01-01

    The SMARTCyp server is the first web application for site of metabolism prediction of cytochrome P450-mediated drug metabolism.......The SMARTCyp server is the first web application for site of metabolism prediction of cytochrome P450-mediated drug metabolism....

  1. Purification and immunochemical detections of ?-naphthoflavone- and phenobarbital-induced avian cytochrome P450 enzymes

    Brown, R.L.; Levi, P.E.; Hodgson, E.; Melancon, M.J.

    1996-01-01

    Livers from mallards (Anas platyrhynchos) were treated with either -naphthoflavone (50 mg/kg) or phenobarbital (70 mg/kg). Purification of induced hepatic cytochrome P450 was accomplished using both DEAE and hydroxyapatite columns, as well as sodium dodecyl sulfate polyacrylamide gel electrophoresis separation. Polyclonal antibodies to these proteins were then produced in young male New Zealand White rabbits. ?-naphthoflavone (?NF)- and phenobarbital(PB)-treated red-winged blackbird, screech owl, European starling and lesser scaup liver microsomes were analyzed in western blots for species cross-reactivity. Although all four of these avian species exhibited cross-reactivity with antibodies to ?NF-induced mallard P450, all but the lesser scaup revealed a protein of higher molecular weight than that of the ?NF-induced mallard. In addition, only the lesser scaup exhibited cross-reactivity with the anti-PB-induced mallard P450 antibodies.

  2. Diabetes and Hepatitis B Vaccination

    Diabetes and Hepatitis B Vaccination Information for Diabetes Educators What is hepatitis B? Hepatitis B is a contagious liver disease that results from infection with the hepatitis B virus. When first infected, a person can develop ...

  3. Hepatitis Information for the Public

    ... Hepatitis Contact Us Anonymous Feedback Quick Links to Hepatitis … A | B | C | D | E Viral Hepatitis Home ... Local Partners & Grantees Policy and Programs Resource Center Hepatitis Information for the Public Recommend on Facebook Tweet ...

  4. Immunoglobulins for preventing hepatitis A

    Liu, Jian Ping; Nikolova, Dimitrinka; Fei, Yutong

    2009-01-01

    Hepatitis A (infectious hepatitis) is a common epidemic disease. Immunoglobulins for passive immunisation are used as prevention.......Hepatitis A (infectious hepatitis) is a common epidemic disease. Immunoglobulins for passive immunisation are used as prevention....

  5. Low dose trichloroethylene alters cytochrome P450 - 2C subfamily expression in the developing chick heart

    Makwana, Om; Ahles, Lauren; Lencinas, Alejandro; Selmin, Ornella I.; Runyan, Raymond B.

    2013-01-01

    Trichloroethylene (TCE) is an organic solvent and common environmental contaminant. TCE exposure is associated with heart defects in humans and animal models. Primary metabolism of TCE in adult rodent models is by specific hepatic cytochrome P450 enzymes (Lash et al., 2000). As association of TCE exposure with cardiac defects is in exposed embryos prior to normal liver development, we investigated metabolism of TCE in the early embryo. Developing chick embryos were dosed in ovo with environmentally relevant doses of TCE (8 ppb and 800 ppb) and RNA was extracted from cardiac and extra-cardiac tissue (whole embryo without heart). Real time PCR showed upregulation of CYP2H1 transcripts in response to TCE exposure in the heart. No detectable cytochrome expression was found in extra-cardiac tissue. As seen previously, the dose response was non-monotonic and 8ppb elicited stronger upregulation than 800 ppb. Immunostaining for CYP2C subfamily expression confirmed protein expression and showed localization in both myocardium and endothelium. TCE exposure increased protein expression in both tissues. These data demonstrate that the earliest embryonic expression of phase I detoxification enzymes is in the developing heart. Expression of these CYPs is likely to be relevant to the susceptibility of the developing heart to environmental teratogens. PMID:22855351

  6. Anti-liver-kidney microsome antibody type 1 recognizes human cytochrome P450 db1.

    Gueguen, M; Yamamoto, A M; Bernard, O; Alvarez, F

    1989-03-15

    Anti-liver-kidney microsome antibody type 1 (LKM1), present in the sera of a group of children with autoimmune hepatitis, was recently shown to recognize a 50 kDa protein identified as rat liver cytochromes P450 db1 and db2. High homology between these two members of the rat P450 IID subfamily and human P450 db1 suggested that anti-LKM1 antibody is directed against this human protein. To test this hypothesis, a human liver cDNA expression library in phage lambda GT-11 was screened using rat P450 db1 cDNA as a probe. Two human cDNA clones were found to be identical to human P450 db1 by restriction mapping. Immunoblot analysis using as antigen, the purified fusion protein from one of the human cDNA clones showed that only anti-LKM1 with anti-50 kDa reactivity recognized the fusion protein. This fusion protein was further used to develop an ELISA test that was shown to be specific for sera of children with this disease. These results: 1) identify the human liver antigen recognized by anti-LKM1 auto-antibodies as cytochrome P450 db1, 2) allow to speculate that mutation on the human P450 db1 gene could alter its expression in the hepatocyte and make it auto-antigenic, 3) provide a simple and specific diagnostic test for this disease.

  7. Microbiological diagnostics of viral hepatitis

    HASDEMİR, Ufuk

    2016-01-01

    Viral hepatitis is an infection that primarily affects the liverbut may also have systemic clinical manifestations. The vastmajority of viral hepatitis are caused by one of five hepatotropicviruses: hepatitis A virus (HAV), hepatitis B virus (HBV),hepatitis C virus (HCV), hepatitis D (delta) virus (HDV), andhepatitis E virus (HEV) (Table I) [1]. HBV, HCV, and HDValso cause chronic hepatitis, whereas HAV does not. HEVcauses acute hepatitis in normal hosts but can cause protractedand chronic he...

  8. [Viral hepatitis in travellers].

    Abreu, Cândida

    2007-01-01

    Considering the geographical asymmetric distribution of viral hepatitis A, B and E, having a much higher prevalence in the less developed world, travellers from developed countries are exposed to a considerable and often underestimated risk of hepatitis infection. In fact a significant percentage of viral hepatitis occurring in developed countries is travel related. This results from globalization and increased mobility from tourism, international work, humanitarian and religious missions or other travel related activities. Several studies published in Europe and North America shown that more than 50% of reported cases of hepatitis A are travel related. On the other hand frequent outbreaks of hepatitis A and E in specific geographic areas raise the risk of infection in these restricted zones and that should be clearly identified. Selected aspects related with the distribution of hepatitis A, B and E are reviewed, particularly the situation in Portugal according to the published studies, as well as relevant clinical manifestations and differential diagnosis of viral hepatitis. Basic prevention rules considering enteric transmitted hepatitis (hepatitis A and hepatitis E) and parenteral transmitted (hepatitis B) are reviewed as well as hepatitis A and B immunoprophylaxis. Common clinical situations and daily practice "pre travel" advice issues are discussed according to WHO/CDC recommendations and the Portuguese National Vaccination Program. Implications from near future availability of a hepatitis E vaccine, a currently in phase 2 trial, are highlighted. Potential indications for travellers to endemic countries like India, Nepal and some regions of China, where up to 30% of sporadic cases of acute viral hepatitis are caused by hepatitis E virus, are considered. Continued epidemiological surveillance for viral hepatitis is essential to recognize and control possible outbreaks, but also to identify new viral hepatitis agents that may emerge as important global health

  9. Adaptive immunity in autoimmune hepatitis.

    Longhi, Maria Serena; Ma, Yun; Mieli-Vergani, Giorgina; Vergani, Diego

    2010-01-01

    The histological lesion of interface hepatitis, with its dense portal cell infiltrate consisting of lymphocytes, monocytes/macrophages and plasma cells, was the first to suggest an autoaggressive cellular immune attack in the pathogenesis of autoimmune hepatitis (AIH). Immunohistochemical studies, focused on the phenotype of inflammatory cells infiltrating the liver parenchyma, have shown a predominance of alphabeta-T cells. Amongst these cells, the majority have been CD4 helper/inducers, while a sizeable minority have consisted of CD8 cytotoxic/suppressors. Lymphocytes on non-T cell lineage included natural killer cells, monocytes/macrophages and B lymphocytes. For autoimmunity to arise, the self-antigenic peptide, embraced by an human leukocyte antigen (HLA) class II molecule, must be presented to an uncommitted T helper (T(H)0) lymphocyte by professional antigen-presenting cells. Once activated and according to the presence in the milieu of interleukin 12 (IL-12) or IL-4, T(H)0 lymphocytes can differentiate into T(H)1 cells, which are pivotal to macrophage activation; enhance HLA class I expression, rendering liver cells vulnerable to CD8 T-cell attack; and induce HLA class II expression on hepatocytes; or they can differentiate into T(H)2 cells, which produce IL-4, IL-10 and IL-13, cytokines favouring autoantibody production by B lymphocytes. Autoantigen recognition is tightly controlled by regulatory mechanisms, such as those exerted by CD4+CD25(high) regulatory T cells. Numerical and functional regulatory T cell impairment characterises AIH and permits the perpetuation of effector immune responses with ensuing persistent liver destruction. Advances in the study of autoreactive T cells stem mostly from AIH type 2, where the main autoantigen, cytochrome P450IID6 (CYP2D6), is known to enable characterisation of antigen-specific immune responses. Copyright 2010 S. Karger AG, Basel.

  10. Cytochrome P450-Mediated Phytoremediation using Transgenic Plants: A Need for Engineered Cytochrome P450 Enzymes

    Kumar, Santosh; Jin, Mengyao; Weemhoff, James L

    2012-01-01

    There is an increasing demand for versatile and ubiquitous Cytochrome P450 (CYP) biocatalysts for biotechnology, medicine, and bioremediation. In the last decade there has been an increase in realization of the power of CYP biocatalysts for detoxification of soil and water contaminants using transgenic plants. However, the major limitations of mammalian CYP enzymes are that they require CYP reductase (CPR) for their activity, and they show relatively low activity, stability, and expression. O...

  11. Flower colour and cytochromes P450.

    Tanaka, Yoshikazu; Brugliera, Filippa

    2013-02-19

    Cytochromes P450 play important roles in biosynthesis of flavonoids and their coloured class of compounds, anthocyanins, both of which are major floral pigments. The number of hydroxyl groups on the B-ring of anthocyanidins (the chromophores and precursors of anthocyanins) impact the anthocyanin colour, the more the bluer. The hydroxylation pattern is determined by two cytochromes P450, flavonoid 3'-hydroxylase (F3'H) and flavonoid 3',5'-hydroxylase (F3'5'H) and thus they play a crucial role in the determination of flower colour. F3'H and F3'5'H mostly belong to CYP75B and CYP75A, respectively, except for the F3'5'Hs in Compositae that were derived from gene duplication of CYP75B and neofunctionalization. Roses and carnations lack blue/violet flower colours owing to the deficiency of F3'5'H and therefore lack the B-ring-trihydroxylated anthocyanins based upon delphinidin. Successful redirection of the anthocyanin biosynthesis pathway to delphinidin was achieved by expressing F3'5'H coding regions resulting in carnations and roses with novel blue hues that have been commercialized. Suppression of F3'5'H and F3'H in delphinidin-producing plants reduced the number of hydroxyl groups on the anthocyanidin B-ring resulting in the production of monohydroxylated anthocyanins based on pelargonidin with a shift in flower colour to orange/red. Pelargonidin biosynthesis is enhanced by additional expression of a dihydroflavonol 4-reductase that can use the monohydroxylated dihydrokaempferol (the pelargonidin precursor). Flavone synthase II (FNSII)-catalysing flavone biosynthesis from flavanones is also a P450 (CYP93B) and contributes to flower colour, because flavones act as co-pigments to anthocyanins and can cause blueing and darkening of colour. However, transgenic plants expression of a FNSII gene yielded paler flowers owing to a reduction of anthocyanins because flavanones are precursors of anthocyanins and flavones.

  12. Hepatitis virus panel

    ... page: //medlineplus.gov/ency/article/003558.htm Hepatitis virus panel To use the sharing features on this page, please enable JavaScript. The hepatitis virus panel is a series of blood tests used ...

  13. Hepatitis B - children

    ... B children; HBV children; Pregnancy - hepatitis B children; Maternal transmission - hepatitis B children ... growth and development. Regular monitoring plays an important role in managing the disease in children. You should ...

  14. Hepatitis E Virus

    Before the discovery of hepatitis E virus (HEV), many epidemics of hepatitis in ... HEV was discovered in 1983 in the ... HEV infection is increased by HIV infection in pregnancy. (Caron et al. .... immunosuppressive therapy on the natural history.

  15. Delta agent (Hepatitis D)

    ... this page: //medlineplus.gov/ency/article/000216.htm Hepatitis D (Delta agent) To use the sharing features on this page, please enable JavaScript. Hepatitis D is a viral infection caused by the ...

  16. Hepatitis A Test

    ... Links Patient Resources For Health Professionals Subscribe Search Hepatitis A Testing Send Us Your Feedback Choose Topic At ... IgG HAV-Ab total Anti-HAV Formal Name Viral Hepatitis A Antibody This article was last reviewed on ...

  17. Hepatic falciform artery

    Jaques, Paul F.; Mauro, Matthew A.; Sandhu, Jeet

    1997-01-01

    The hepatic falciform artery is an occasional terminal branch of the left or middle hepatic artery, and may provide an uncommon but important collateral route when the principal visceral arteries are occluded

  18. Hepatitis A -- children

    ... this page: //medlineplus.gov/ency/article/007670.htm Hepatitis A - children To use the sharing features on this page, please enable JavaScript. Hepatitis A in children is swelling and inflamed tissue of ...

  19. Hepatitis B Foundation Newsletter: B Informed

    ... Clinical Trials Physician Directory HBV Meeting What Is Hepatitis B? What Is Hepatitis B? The ABCs of Viral Hepatitis Liver Cancer and Hepatitis B Hepatitis Delta Coinfection Hepatitis C Coinfection HIV/AIDS ...

  20. Surveillance for Viral Hepatitis - United States, 2014

    ... Resource Center Anonymous Feedback Viral Hepatitis Surveillance for Viral Hepatitis – United States, 2014 Recommend on Facebook Tweet Share ... Cases Hepatitis A Hepatitis B Hepatitis C Discussion Hepatitis A virus Index PAGE DESCRIPTION Table 2.1 Reported ...

  1. Aberrant hepatic artery

    Konstam, M.A.; Novelline, R.A.; Athanasoulis, C.A.

    1979-01-01

    In a patient undergoing selective hepatic arteriography for suspected liver trauma, a nonopacified area of the liver, initially thought to represent a hepatic hematoma, was later discovered to be due to the presence of an accessory right hepatic artery arising from the superior mesenteric artery. This case illustrates the need for a search for aberrant vasculature whenever a liver hematoma is suspected on the basis of a selective hepatic arteriogram. (orig.) [de

  2. Protective effect of tea polyphenols against paracetamol-induced hepatotoxicity in mice is significantly correlated with cytochrome P450 suppression.

    Chen, Xia; Sun, Chang-Kai; Han, Guo-Zhu; Peng, Jin-Yong; Li, Ying; Liu, Yan-Xia; Lv, Yuan-Yuan; Liu, Ke-Xin; Zhou, Qin; Sun, Hui-Jun

    2009-04-21

    To investigate the hepatoprotective activity of tea polyphenols (TP) and its relation with cytochrome P450 (CYP450) expression in mice. Hepatic CYP450 and CYPb(5) levels were measured by UV-spectrophotometry in mice 2 d after intraperitoneal TP (25, 50 and 100 mg/kg per day). Then the mice were intragastricly pre-treated with TP (100, 200 and 400 mg/kg per day) for six days before paracetamol (1000 mg/kg) was given. Their acute mortality was compared with that of control mice. The mice were pre-treated with TP (100, 200, and 400 mg/kg per day) for five days before paracetamol (500 mg/kg) was given. Hepatic CYP2E1 and CYP1A2 protein and mRNA expression levels were evaluated by Western blotting, immunohistochemical staining and transcriptase-polymerase chain reaction. The hepatic CYP450 and CYPb(5) levels in mice of TP-treated groups (100, 200 and 400 mg/kg per day) were decreased in a dose-dependent manner compared with those in the negative control mice. TP significantly attenuated the paracetamol-induced hepatic injury and dramatically reduced the mortality of paracetamol-treated mice. Furthermore, TP reduced CYP2E1 and CYP1A2 expression at both protein and mRNA levels in a dose-dependent manner. TP possess potential hepatoprotective properties and can suppress CYP450 expression.

  3. Hepatitis viruses overview

    Hepatitis is major cause of morbidity or mortality worldwide, particularly in the developing world. The major causes of infective hepatitis are hepatitis viruses. A, B, C, D or E. In the acute phase, there are no clinical features that can reliably differentiate between these viruses. Infection may be asymptomatic or can present as.

  4. Hepatitis B Test

    ... Links Patient Resources For Health Professionals Subscribe Search Hepatitis B Testing Send Us Your Feedback Choose Topic At ... Known As HBV Tests Hep B anti-HBs Hepatitis B Surface Antibody HBsAg Hepatitis B Surface Antigen HBeAg ...

  5. NMR comparison of prokaryotic and eukaryotic cytochromes c

    Chau, Meihing; Cai, Meng Li; Timkovich, R.

    1990-01-01

    1 H NMR spectroscopy has been used to examine ferrocytochrome c-551 from Pseudomonas aeruginosa (ATCC 19429) over the pH range 3.5-10.6 and the temperature range 4-60 degree C. Resonance assignments are proposed for main-chain and side-chain protons. Comparison of results for cytochrome c-551 to recently assigned spectra for horse cytochrome c and mutants of yeast iso-1 cytochrome reveals some unique resonances with unusual chemical shifts in all cytochromes that may serve as markers for the heme region. Results for cytochrome c-551 indicate that in the smaller prokaryotic cytochrome, all benzoid side chains are rapidly flipping on the NMR time scale. In contrast, in eukaryotic cytochromes there are some rings flipping slowly on the NMR time scale. The ferrocytochrome c-551 undergoes a transition linked to pH with a pK around 7. The pH behavior of assigned resonances provides evidence that the site of protonation is the inner or buried 17-propionic acid heme substituent (IUPAC-IUB porphyrin nomenclature). Conformational heterogeneity has been observed for segments near the inner heme propionate substituent

  6. Calcium transport in vesicles energized by cytochrome oxidase

    Rosier, Randy N. [Univ. of Rochester, NY (United States)

    1979-01-01

    Experiments on the reconstitution of cytochrome oxidase into phospholipid vesicles were carried out using techniques of selectivity energizing the suspensions with ascorbate and cytochrome c or ascorbate, PMS, and internally trapped cytochrome c. It was found that the K+ selective ionophore valinomycin stimulated the rate of respiration of cytochrome oxidase vesicles regardless of the direction of the K+ flux across the vesicle membranes. The stimulation occurred in the presence of protonophoric uncouplers and in the complete absence of potassium or in detergent-lysed suspensions. Gramicidin had similar effects and it was determined that the ionophores acted by specific interaction with cytochrome oxidase rather than by the previously assumed collapse of membrane potentials. When hydrophobic proteins and appropriate coupling factors were incorporated into the cytochrome oxidase, vesicles phosphorylation of ADP could be coupled to the oxidation reaction of cytochrome oxidase. Relatively low P:O, representing poor coupling of the system, were problematical and precluded measurements of protonmotive force. However the system was used to study ion translocation.

  7. Biogenesis of the yeast cytochrome bc1 complex.

    Zara, Vincenzo; Conte, Laura; Trumpower, Bernard L

    2009-01-01

    The mitochondrial respiratory chain is composed of four different protein complexes that cooperate in electron transfer and proton pumping across the inner mitochondrial membrane. The cytochrome bc1 complex, or complex III, is a component of the mitochondrial respiratory chain. This review will focus on the biogenesis of the bc1 complex in the mitochondria of the yeast Saccharomyces cerevisiae. In wild type yeast mitochondrial membranes the major part of the cytochrome bc1 complex was found in association with one or two copies of the cytochrome c oxidase complex. The analysis of several yeast mutant strains in which single genes or pairs of genes encoding bc1 subunits had been deleted revealed the presence of a common set of bc1 sub-complexes. These sub-complexes are represented by the central core of the bc1 complex, consisting of cytochrome b bound to subunit 7 and subunit 8, by the two core proteins associated with each other, by the Rieske protein associated with subunit 9, and by those deriving from the unexpected interaction of each of the two core proteins with cytochrome c1. Furthermore, a higher molecular mass sub-complex is that composed of cytochrome b, cytochrome c1, core protein 1 and 2, subunit 6, subunit 7 and subunit 8. The identification and characterization of all these sub-complexes may help in defining the steps and the molecular events leading to bc1 assembly in yeast mitochondria.

  8. Control of electron transfer in the cytochrome system of mitochondria by pH, transmembrane pH gradient and electrical potential. The cytochromes b-c segment.

    Papa, S; Lorusso, M; Izzo, G; Capuano, F

    1981-02-15

    1. A study is presented of the effects of pH, transmembrane pH gradient and electrical potential on oxidoreductions of b and c cytochromes in ox heart mitochondria and 'inside-out' submitochondrial particles. 2. Kinetic analysis shows that, in mitochondria at neutral pH, there is a restraint on the aerobic oxidation of cytochrome b566 with respect to cytochrome b562. Valinomycin plus K+ accelerates cytochrome b566 oxidation and retards net oxidation of cytochrome b562. At alkaline pH the rate of cytochrome b566 oxidation approaches that of cytochrome b562 and the effects of valinomycin on b cytochromes are impaired. 3. At slightly acidic pH, oxygenation of antimycin-supplemented mitochondria causes rapid reduction of cytochrome b566 and small delayed reduction of cytochrome b562. Valinomycin or a pH increase in the medium promote reduction of cytochrome b562 and decrease net reduction of cytochrome b566. 4. Addition of valinomycin to mitochondria and submitochondrial particles in the respiring steady state causes, at pH values around neutrality, preferential oxidation of cytochrome b566 with respect to cytochrome b562. The differential effect of valinomycin on oxidation of cytochromes b566 and b562 is enhanced by substitution of 1H2O of the medium with 2H2O and tends to disappear as the pH of the medium is raised to alkaline values. 5. Nigericin addition in the aerobic steady state causes, both in mitochondria and submitochondrial particles, preferential oxidation of cytochrome b562 with respect to cytochrome b566. This is accompanied by c cytochrome oxidation in mitochondria but c cytochrome reduction in submitochondrial particles. 6. In mitochondria as well as in submitochondrial particles, the aerobic transmembrane potential (delta psi) does not change by raising the pH of the external medium from neutrality to alkalinity. The transmembrane pH gradient (delta pH) on the other hand, decrease slightly. 7. The results presented provide evidence that the delta psi

  9. Plastocyanin/cytochrome c6 interchange in Scenedesmus vacuolatus.

    Miramar, M Dolores; Inda, Luis A; Saraiva, Lígia M; Peleato, M Luisa

    2003-12-01

    Plastocyanin and cytochrome c6 from the green alga Scenedesmus vacuolatus were immunoquantified in cells grown under different concentrations of copper and iron. Plastocyanin expression was constitutive, its synthesis was not significantly affected by iron availability, and increases with copper availability. On the contrary, cytochrome c6 synthesis is repressed by copper, and only residual amounts of the protein were detected at 0.1 micromol/L copper. Under copper deficiency, cytochrome c6 is slightly dependent on iron. In natural environments, plastocyanin seems to be the predominant electron donor to P700.

  10. Alcoholic hepatitis.

    Damgaard Sandahl, Thomas

    2014-10-01

    Alcoholic hepatitis (AH) is an acute inflammatory syndrome causing significant morbidity and mortality. The prognosis is strongly dependent on disease severity, as assessed by clinical scoring systems. Reliable epidemiological data as well as knowledge of the clinical course of AH are essential for planning and resource allocation within the health care system. Likewise, individual evaluation of risk is desirable in the clinical handling of patients with AH as it can guide treatment, improve patient information, and serve as strata in clinical trials. The present PhD thesis is based on three studies using a cohort of nearly 2000 patients diagnosed with AH in Denmark from 1999 to 2008 as a cohort, in a population-based study design. The aims of this thesis were as follows. (1) To describe the incidence and short- and long-term mortality, of AH in Denmark (Study I). (2) To validate and compare the ability of the currently available prognostic scores to predict mortality in AH (Study II). (3) To investigate the short- and long-term causes of death of patients with AH (Study III). During the study decade, the annual incidence rate in the Danish population rose from 37 to 46 per 106 for men and from 24 to 34 per 106 for women. Both short- and long-term mortality rose for men and women, and the increase in short-term mortality was attributable to increasing patient age and prevalence of cirrhosis. Our evaluation of the most commonly used prognostic scores for predicting the mortality of patients with AH showed that all scores performed similarly, with Area under the Receiver Operator Characteristics curves giving values between 0.74 and 0.78 for 28-day mortality assessed on admission. Our study on causes of death showed that in the short-term (thesis provides novel warranted epidemiological information about AH that shows increasing incidence and mortality rates. Consequently, it reiterates the fact that AH is a life-threatening disease and suggests that AH is an

  11. Pathogenesis of Hepatic Encephalopathy

    Irena Ciećko-Michalska

    2012-01-01

    Full Text Available Hepatic encephalopathy can be a serious complication of acute liver failure and chronic liver diseases, predominantly liver cirrhosis. Hyperammonemia plays the most important role in the pathogenesis of hepatic encephalopathy. The brain-blood barrier disturbances, changes in neurotransmission, neuroinflammation, oxidative stress, GABA-ergic or benzodiazepine pathway abnormalities, manganese neurotoxicity, brain energetic disturbances, and brain blood flow abnormalities are considered to be involved in the development of hepatic encephalopathy. The influence of small intestine bacterial overgrowth (SIBO on the induction of minimal hepatic encephalopathy is recently emphasized. The aim of this paper is to present the current views on the pathogenesis of hepatic encephalopathy.

  12. Pathogenesis of Hepatic Encephalopathy

    Ciećko-Michalska, Irena; Szczepanek, Małgorzata; Słowik, Agnieszka; Mach, Tomasz

    2012-01-01

    Hepatic encephalopathy can be a serious complication of acute liver failure and chronic liver diseases, predominantly liver cirrhosis. Hyperammonemia plays the most important role in the pathogenesis of hepatic encephalopathy. The brain-blood barrier disturbances, changes in neurotransmission, neuroinflammation, oxidative stress, GABA-ergic or benzodiazepine pathway abnormalities, manganese neurotoxicity, brain energetic disturbances, and brain blood flow abnormalities are considered to be involved in the development of hepatic encephalopathy. The influence of small intestine bacterial overgrowth (SIBO) on the induction of minimal hepatic encephalopathy is recently emphasized. The aim of this paper is to present the current views on the pathogenesis of hepatic encephalopathy. PMID:23316223

  13. Aspirin Induces Apoptosis through Release of Cytochrome c from Mitochondria

    Katja C. Zimmermann

    2000-01-01

    Full Text Available Nonsteroidal anti-inflammatory drugs (NSAID reduce the risk for cancer, due to their anti proliferative and apoptosis-inducing effects. A critical pathway for apoptosis involves the release of cytochrome c from mitochondria, which then interacts with Apaf-1 to activate caspase proteases that orchestrate cell death. In this study we found that treatment of a human cancer cell line with aspirin induced caspase activation and the apoptotic cell morphology, which was blocked by the caspase inhibitor zVAD-fmk. Further analysis of the mechanism underlying this apoptotic event showed that aspirin induces translocation of Bax to the mitochondria and triggers release of cytochrome c into the cytosol. The release of cytochrome c from mitochondria was inhibited by overexpression of the antiapoptotic protein Bcl-2 and cells that lack Apaf-1 were resistant to aspirin-induced apoptosis. These data provide evidence that the release of cytochrome c is an important part of the apoptotic mechanism of aspirin.

  14. Cytochrome c Is Tyrosine 97 Phosphorylated by Neuroprotective Insulin Treatment

    Sanderson, T. H.; Mahapatra, G.; Pecina, Petr; Ji, Q.; Yu, K.; Sinkler, Ch.; Varughese, A.; Kumar, R.; Bukowski, M. J.; Tousignant, R. N.; Salomon, A. R.; Lee, I.; Hüttemann, M.

    2013-01-01

    Roč. 8, č. 11 (2013), e78627 E-ISSN 1932-6203 Institutional support: RVO:67985823 Keywords : cytochrome c * tyrosine phosphorylation * brain ischemia * insulin Subject RIV: ED - Physiology Impact factor: 3.534, year: 2013

  15. North African genetic variation of cytochrome and sulfotransferase ...

    in these genes have shown relevant ethnic differences among Sub-Saharan .... This cytochrome catalyzes a big amount of oxidative reactions of substances like ... with samples of European and African origin (because of the scarce data ...

  16. Isolation and purification of membrane-bound cytochrome c from ...

    Administrator

    2007-05-02

    ferrochrome and redox spectra showed the presence of heme-c. Key words: Cytochrome c, respiratory chain and Proteus mirabilis. INTRODUCTION. Proteus mirabilis is facultative anaerobic, rod-shaped, gram negative bacterium.

  17. Oxygen and xenobiotic reductase activities of cytochrome P450.

    Goeptar, A.R.; Scheerens, H.; Vermeulen, N.P.E.

    1995-01-01

    The oxygen reductase and xenobiotic reductase activities of cytochrome P450 (P450) are reviewed. During the oxygen reductase activity of P450, molecular oxygen is reduced to superoxide anion radicals (O

  18. The biodiversity of microbial cytochromes P450.

    Kelly, Steven L; Lamb, David C; Jackson, Colin J; Warrilow, Andrew G; Kelly, Diane E

    2003-01-01

    The cytochrome P450 (CYP) superfamily of genes and proteins are well known for their involvement in pharmacology and toxicology, but also increasingly for their importance and diversity in microbes. The extent of diversity has only recently become apparent with the emergence of data from whole genome sequencing projects and the coming years will reveal even more information on the diversity in microbial eukaryotes. This review seeks to describe the historical development of these studies and to highlight the importance of the genes and proteins. CYPs are deeply involved in the development of strategies for deterrence and attraction as well as detoxification. As such, there is intense interest in pathways of secondary metabolism that include CYPs in oxidative tailoring of antibiotics, sometimes influencing potency as bioactive compounds. Further to this is interest in CYPs in metabolism of xenobiotics for use as carbon sources for microbial growth and as biotransformation agents or in bioremediation. CYPs are also current and potential drug targets; compounds inhibiting CYP are antifungal and anti-protozoan agents, and potentially similar compounds may be useful against some bacterial diseases such as tuberculosis. Of note is the diversity of CYP requirements within an organism, ranging from Escherichia coli that has no CYPs as in many bacteria, to Mycobacterium smegmatis that has 40 representing 1% of coding genes. The basidiomycete fungus Phanerochaete chrysosporium surprised all when it was found to contain a hundred or more CYPs. The functional genomic investigation of these orphan CYPs is a major challenge for the future.

  19. Geometrical analysis of cytochrome c unfolding

    Urie, Kristopher G.; Pletneva, Ekaterina; Gray, Harry B.; Winkler, Jay R.; Kozak, John J.

    2011-01-01

    A geometrical model has been developed to study the unfolding of iso-1 cytochrome c. The model draws on the crystallographic data reported for this protein. These data were used to calculate the distance between specific residues in the folded state, and in a sequence of extended states defined by n = 3, 5, 7, 9, 11, 13, and 15 residue units. Exact calculations carried out for each of the 103 residues in the polypeptide chain demonstrate that different regions of the chain have different unfolding histories. Regions where there is a persistence of compact structures can be identified, and this geometrical characterization is fully consistent with analyses of time-resolved fluorescence energy-transfer (TrFET) data using dansyl-derivatized cysteine side-chain probes at positions 39, 50, 66, 85, and 99. The calculations were carried out assuming that different regions of the polypeptide chain unfold synchronously. To test this assumption, lattice Monte Carlo simulations were performed to study systematically the possible importance of asynchronicity. Calculations show that small departures from synchronous dynamics can arise if displacements of residues in the main body of the chain are much more sluggish than near-terminal residues.

  20. Epidermal CYP2 family cytochromes P450

    Du Liping; Hoffman, Susan M.G.; Keeney, Diane S.

    2004-01-01

    Skin is the largest and most accessible drug-metabolizing organ. In mammals, it is the competent barrier that protects against exposure to harmful stimuli in the environment and in the systemic circulation. Skin expresses many cytochromes P450 that have critical roles in exogenous and endogenous substrate metabolism. Here, we review evidence for epidermal expression of genes from the large CYP2 gene family, many of which are expressed preferentially in extrahepatic tissues or specifically in epithelia at the environmental interface. At least 13 CYP2 genes (CYP2A6, 2A7, 2B6, 2C9, 2C18, 2C19, 2D6, 2E1, 2J2, 2R1, 2S1, 2U1, and 2W1) are expressed in skin from at least some human individuals, and the majority of these genes are expressed in epidermis or cultured keratinocytes. Where epidermal expression has been localized in situ by hybridization or immunocytochemistry, CYP2 transcripts and proteins are most often expressed in differentiated keratinocytes comprising the outer (suprabasal) cell layers of the epidermis and skin appendages. The tissue-specific transcriptional regulation of CYP2 genes in the epidermis, and in other epithelia that interface with the environment, suggests important roles for at least some CYP2 gene products in the production and disposition of molecules affecting competency of the epidermal barrier

  1. Polyethylene glycol promotes autoxidation of cytochrome c.

    Sato, Wataru; Uchida, Takeshi; Saio, Tomohide; Ishimori, Koichiro

    2018-06-01

    Cytochrome c (Cyt c) was rapidly oxidized by molecular oxygen in the presence, but not absence of PEG. The redox potential of heme c was determined by the potentiometric titration to be +236 ± 3 mV in the absence of PEG, which was negatively shifted to +200 ± 4 mV in the presence of PEG. The underlying the rapid oxidation was explored by examining the structural changes in Cyt c in the presence of PEG using UV-visible absorption, circular dichroism, resonance Raman, and fluorescence spectroscopies. These spectroscopic analyses suggested that heme oxidation was induced by a modest tertiary structural change accompanied by a slight shift in the heme position (c, which triggered heme displacement. The primary dehydration site was estimated to be around surface-exposed hydrophobic residues near the heme center: Ile81 and Val83. These findings and our previous studies, which showed that hydrated water molecules around Ile81 and Val83 are expelled when Cyt c forms a complex with CcO, proposed that dehydration of these residues is functionally significant to electron transfer from Cyt c to CcO. Copyright © 2018 Elsevier B.V. All rights reserved.

  2. Pharmacokinetics and Differential Regulation of Cytochrome P450 Enzymes in Type 1 Allergic Mice.

    Tanino, Tadatoshi; Komada, Akira; Ueda, Koji; Bando, Toru; Nojiri, Yukie; Ueda, Yukari; Sakurai, Eiichi

    2016-12-01

    Type 1 allergic diseases are characterized by elevated production of specific immunoglobulin E (IgE) for each antigen and have become a significant health problem worldwide. This study investigated the effect of IgE-mediated allergy on drug pharmacokinetics. To further understand differential suppression of hepatic cytochrome P450 (P450) activity, we examined the inhibitory effect of nitric oxide (NO), a marker of allergic conditions. Seven days after primary sensitization (PS7) or secondary sensitization (SS7), hepatic CYP1A2, CYP2C, CYP2E1, and CYP3A activities were decreased to 45%-75% of the corresponding control; however, CYP2D activity was not downregulated. PS7 and SS7 did not change the expression levels of five P450 proteins. Disappearance of CYP1A2 and CYP2D substrates from the plasma was not significantly different between allergic mice and control mice. In contrast, the area under the curve of a CYP1A2-mediated metabolite in PS7 and SS7 mice was reduced by 50% of control values. Total clearances of a CYP2E1 substrate in PS7 and SS7 mice were significantly decreased to 70% and 50% respectively, of the control without altering plasma protein binding. Hepatic amounts of CYP1A2 and CYP2E1 substrates were enhanced by allergic induction, being responsible for each downregulated activity. NO scavenger treatment completely improved the downregulated P450 activities. Therefore, our data suggest that the onset of IgE-mediated allergy alters the pharmacokinetics of major P450-metabolic capacity-limited drugs except for CYP2D drugs. NO is highly expected to participate in regulatory mechanisms of the four P450 isoforms. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  3. Solution NMR study of the yeast cytochrome c peroxidase: cytochrome c interaction

    Volkov, Alexander N., E-mail: ovolkov@vub.ac.be; Nuland, Nico A. J. van [Vrije Universiteit Brussel, Jean Jeener NMR Centre, Structural Biology Brussels (Belgium)

    2013-07-15

    Here we present a solution NMR study of the complex between yeast cytochrome c (Cc) and cytochrome c peroxidase (CcP), a paradigm for understanding the biological electron transfer. Performed for the first time, the CcP-observed heteronuclear NMR experiments were used to probe the Cc binding in solution. Combining the Cc- and CcP-detected experiments, the binding interface on both proteins was mapped out, confirming that the X-ray structure of the complex is maintained in solution. Using NMR titrations and chemical shift perturbation analysis, we show that the interaction is independent of the CcP spin-state and is only weakly affected by the Cc redox state. Based on these findings, we argue that the complex of the ferrous Cc and the cyanide-bound CcP is a good mimic of the catalytically-active Cc-CcP compound I species. Finally, no chemical shift perturbations due to the Cc binding at the low-affinity CcP site were observed at low ionic strength. We discuss possible reasons for the absence of the effects and outline future research directions.

  4. Depuration of PCBS and DDTS in mullet under captivity conditions

    Antunes, P.; Gil, O.; Vale, C. [Inst. Nacional de Investigacao Agraria e das Pescas/IPIMAR, Lisboa (Portugal); Ferreira, M. [ICBAS-Inst. de Ciencias Biomedicas Abel Salazar, Porto (Portugal); Reis-Henriques, M.A. [CIIMAR-Centro Interdisciplinar de Investigacao Marinha e Ambiental, Porto (Portugal)

    2004-09-15

    Fish captured in the coastal zone and estuaries often contains enhanced residues of organochlorine compounds in their tissues, in response to environmental contamination. Residues in fish tissues may be eliminated by different pathways, but most of what is known comes from laboratory studies with species that are exposed to contaminants. In recent years, the importance of ethoxyresorufin O-deethylase (EROD), one of the hepatic cytochrome P-450 dependent monooxidase, has become widely known, and it is increasingly accepted as an indicator of exposure to common organic pollutants. The mullet (Mugil cephalus) from the Douro estuary may present relatively high content of PCBs and DDTs. The objective of this study was to examine the levels of PCBs and DDTs in muscle and liver when individuals are exposed to clean sea water and uncontaminated food, and to evaluate whether this is a feasible option for depuration.

  5. Examination of dialysis patients with the aminophenazone breath test

    Heinrich, H.G.; Adler, D.; Hornak, H.; Wuenschmann, H.J.; Mayer, W.K.

    1989-01-01

    In 12 endstage kidney disease patients (8 without and 4 with liver diseases) the activities of cytochrome P 450 -dependent mixed functional oxidases system (MFO) of the liver were studied by using the 14 C-aminophenazone breath test before and after dialysis. The results showed that uremia seems to have a pressing influence on MFO activity. The activity was only significantly increased after dialysis in the group of patients without liver diseases. The MFO activity was reduced in patients with liver diseases. This is a restriction of the hepatic metabolic demethylation capacity. It is unclear if the 14 C-aminophenazone breath test in dialysis patients is qualified to estimate metabolic capacity of the liver. Differentiation between the influence of uremia and of the liver disease on the alteration of MFO activity cannot be made. (author)

  6. Production and characterization of yeast cytochrome c antibodies; immunological studies of mutants with altered cytochrome c synthesis

    Matner, R.R.

    1980-01-01

    Mutations at the structural gene, CYC1, for iso-1-cytochrome c and at the structural gene, CYC7, for iso-2-cytochrome c can reduce the levels of the respective proteins by varying degrees in Saccharomyces cerevisiae. Mutations at two other loci, cyc2 and cyc3, that are unlinked to either of the structural genes, specifically reduced the levels of both iso-cytochromes c. The cyc2 mutations can cause as low as 10 to 20% of the normal level and cyc3 mutations can cause complete deficiencies. We have explored the possiblity that the CYC2 and CYC3 loci code for maturation functions in the biosynthesis of cytochrome c. The approach used to characterize the nature of the cyc2 and cyc3 induced deficiencies of cytochrome c involved four steps. The results were used to propose possible roles for the CYC2 and CYC3 encoded functions. The CYC3 encoded function is hypothesized to be enzymatic heme attachment. CYC2 may code for a protein that binds and transports apo-cytochrome c through the outer mitochondrial membrane and/or enhances the activity of the heme attachment enzyme

  7. Hepatic encephalopathy. Imaging Findings

    Carrillo, Maria Claudia; Bermudez Munoz, Sonia; J Morillo, Anibal

    2007-01-01

    Hepatic encephalopathy occurs in patients with chronic hepatic insufficiency and can produce abnormalities in the central nervous system, which can be observed in MRI studies. Traditionally, these imaging findings include symmetrical hyper intensities in T1-weighted sequences in the basal ganglia (mainly globus pallidus), involving also the substantia nigra, mesencephalic tegmentum, frontal and occipital cortex. These areas appear of normal intensity in T2-weighted imaging sequences. Other entities that can lead to similar findings include manganese intoxication and type-1 neurofibromatosis. Currently, with the advent of MR spectroscopy, abnormalities in patients with clinical and subclinical hepatic encephalopathy have been described. After hepatic transplantation, hyper intensities of the basal ganglia and the MR spectroscopic findings may disappear within 3 months to 1 year, suggesting a functional, more than a structural damage. This article will demonstrate the MR findings of patients with hepatic encephalopathy due to chronic hepatic insufficiency.

  8. Hepatitis isquémica Ischemic hepatitis

    Marcos Amuchástegui (h

    2006-10-01

    Full Text Available La hepatitis isquémica es una complicación sumamente infrecuente de cirugía cardiovascular. Las biopsias muestran necrosis centrolobulillar. El término de "hepatitis" fue propuesto debido al aumento de transaminasas similar a aquellas de origen infeccioso, e "isquémica" por falla en la perfusión hepática. Posteriormente se definió el término de hepatitis isquémica como cuadro de elevación aguda y reversible (dentro de las 72 horas de transaminasas de hasta 20 veces el valor normal, asociado a trastornos en la perfusión hepática, luego de haber excluido otras causas de hepatitis aguda o daño hepatocelular. Se describe el caso de un paciente de 53 años que consulta por dolor epigástrico de 12 h de evolución sin fiebre, náuseas ni vómitos, resistente a la medicación. Tenía antecedentes inmediatos de reemplazo de válvula aórtica, y estaba anticoagulado. Evolucionó con shock y fallo multiorgánico. El examen evidenció marcada ictericia y signos de taponamiento pericárdico, asociado a un aumento considerable de enzimas hepáticas. Un ecocardiograma informó signos de taponamiento cardíaco y ausencia de disección aórtica. Se decidió pericardiocentesis, extrayéndose 970 cc. de líquido sanguinolento, y hemodiálisis, con notable mejoría de su estado hemodinámico. Los valores enzimáticos disminuyeron. Los marcadores virales fueron negativos.Ischemic hepatitis is an uncommon cardiovascular surgery complication. Hepatic biopsies show centrolobulillar necrosis. The term "hepatitis" was proposed because of a raise in hepatic enzymes similar with infectious disease, and "ischemic" because of failure in hepatic perfusion. Ischemic hepatitis was then defined as an acute and reversible elevation of hepatic enzymes (within 72 h, associated with disturbance in hepatic perfusion after excluding other causes of acute hepatitis. A 53 year-old male presented complaining of a 12 h epigastric pain, without nausea or vomiting, resistant

  9. Cytochrome P450s and molecular epidemiology

    Gonzalez, Frank J.; Gelboin, Harry V.

    1993-03-01

    Cytochrome P450 (P450) represent a superfamily of heme-containing monooxygenases that are found throughout the animal and plant kingdoms and in many microorganisms. A number of these enzymes are involved in biosynthetic pathways of steroid synthesis but in mammals the vast majority of P450s function to metabolize foreign chemicals or xenobiotics. In the classical phase I reactions on the latter, a membrane-bound P450 will hydroxylate a compound, usually hydrophobic in nature, and the hydroxyl group will serve as a substrate for the various transferases or phase II enzymes that attach hydrophilic substituents such as glutathione, sulfate or glucuronic acid. Some chemicals, however, are metabolically-activated by P450s to electrophiles capable of reacting with cellular macromolecules. The cellular concentrations of the chemical and P450, reactivity of the active metabolite with nucleic acid and the repairability of the resultant adducts, in addition to the nature of the cell type, likely determines whether a chemical will be toxic and kill the cell or will transform the cell. Immunocorrelative and cDNA-directed expression have been used to define the substrate specificities of numerous human P450s. Levels of expression of different human P450 forms have been measured by both in vivo and in vitro methodologies leading to the realization that a large degree of interindividual differences occur in P450 expression. Reliable procedures for measuring P450 expression in healthy and diseased subjects will lead to prospective and case- cohort studies to determine whether interindividual differences in levels of P450 are associated with susceptibility or resistance to environmentally-based disease.

  10. Cytochrome b5 reductase is the component from neuronal synaptic plasma membrane vesicles that generates superoxide anion upon stimulation by cytochrome c

    Alejandro K. Samhan-Arias

    2018-05-01

    Full Text Available In this work, we measured the effect of cytochrome c on the NADH-dependent superoxide anion production by synaptic plasma membrane vesicles from rat brain. In these membranes, the cytochrome c stimulated NADH-dependent superoxide anion production was inhibited by antibodies against cytochrome b5 reductase linking the production to this enzyme. Measurement of the superoxide anion radical generated by purified recombinant soluble and membrane cytochrome b5 reductase corroborates the production of the radical by different enzyme isoforms. In the presence of cytochrome c, a burst of superoxide anion as well as the reduction of cytochrome c by cytochrome b5 reductase was measured. Complex formation between both proteins suggests that cytochrome b5 reductase is one of the major partners of cytochrome c upon its release from mitochondria to the cytosol during apoptosis. Superoxide anion production and cytochrome c reduction are the consequences of the stimulated NADH consumption by cytochrome b5 reductase upon complex formation with cytochrome c and suggest a major role of this enzyme as an anti-apoptotic protein during cell death.

  11. Hepatic artery infusion (HAI) for hepatic metastases in combination with hepatic resection and hepatic radiation

    Merrick, H.W.; Dobelbower, R.R.; Ringleint, J.F.; Skeel, R.T.

    1986-01-01

    Renewed interest in hepatic artery infusion has been stimulated by the development of a totally implantable pump which eliminates many of the problems encountered by the external pumps and catheters. As the potential benefit of hepatic artery infusion would be greater if either all gross disease were removed by prior resection, or alternatively, if non-resectable disease were irradiated in conjunction with hepatic artery infusion, the authors initiated a phase I-II trial to evaluate combined modality therapy

  12. Preventing hepatitis B or C

    ... page: //medlineplus.gov/ency/patientinstructions/000401.htm Preventing hepatitis B or C To use the sharing features on this page, please enable JavaScript. Hepatitis B and hepatitis C infections cause irritation and ...

  13. Hepatitis in the United States

    In this podcast, Dr. John Ward, Director of CDC’s Division of Viral Hepatitis, discusses the different types of viral hepatitis and how they can be prevented. He also describes how hepatitis is transmitted and treated.

  14. Primary isolated hepatic tuberculosis

    Sheikh, A.S.F.; Qureshi, I.H.; Saba, K.; Bukhari, M.H.

    2013-01-01

    Isolated hepatic tuberculosis without pulmonary or bowel involvement is a diagnostic challenge and can cause considerable morbidity. A young lady from Lahore presented with fever, pain in right hypochondria, nausea and weight loss. CT scan of abdomen showed multiple small hypodense non-enhancing lesions and a heterogeneous texture of liver. Biopsy confirmed the diagnosis of hepatic tuberculosis. It was concluded a case of isolated hepatic tuberculosis without evidence of other primary sites involvement. It is important to consider tuberculosis in the differential diagnosis when suspecting lymphoproliferative or metastatic diseases in a patient with vague symptoms and abnormal hepatic texture on CT. (author)

  15. Hepatitis A virus antibody

    Novak, J.; Kselikova, M.; Urbankova, J.

    1980-01-01

    A description is presented of a radioimmunoassay designed to prove the presence of the antibody against the hepatitis A virus (HA Ab, anti-Ha) using an Abbott HAVAB set. This proof as well as the proof of the antibody against the nucleus of the hepatitis B virus is based on competition between a normal antibody against hepatitis A virus and a 125 I-labelled antibody for the binding sites of a specific antigen spread all over the surface of a tiny ball; this is then indirect proof of the antibody under investigation. The method is described of reading the results from the number of impulses per 60 seconds: the higher the titre of the antibody against the hepatitis A virus in the serum examined, the lower the activity of the specimen concerned. The rate is reported of incidence of the antibody against the hepatitis A virus in a total of 68 convalescents after hepatitis A; the antibody was found in 94.1%. The immunoglobulin made from the convalescents' plasma showed the presence of antibodies in dilutions as high as 1:250 000 while the comparable ratio for normal immunoglobulin Norga was only 1:2500. Differences are discussed in the time incidence of the antibodies against the hepatitis A virus, the antibodies against the surface antigen of hepatitis B, and the antibody against the nucleus of the hepatitis V virus. (author)

  16. [Antibodies and physiopathogeny of autoimmune hepatitis].

    García-Leiva, Jorge; Ríos-Vaca, Aurelio; Torre-Delgadillo, Aldo

    2003-01-01

    Autoimmune hepatitis (AIH) is an inflammatory disease of unknown cause characterized by periportal hepatitis, increased serum globulins and the presence of certain antibodies. The disorder can be classified in three types. Type 1 AIH is characterized by the presence of antinuclear antibodies (ANA) and smooth muscle autoantibodies (SMA) in up to 70-80% of patients. ANA and SMA can be the only antibodies present in 13 and 33% of cases respectively. Type 2 AIH is defined by the presence of liver and kidney antimicrosomal antibodies (LKM1). Type 2 AIH is the only form of the disease in which the autoantigen has been identified: cytochrome mono-oxygenase (P-450 IID6) CYP2D6. In type 3 AIH the presence of anti-SLA/LP (soluble liver antigen/liver pancreas) targets a cytosolic protein involved in the incorporation of selenocysteine into peptidic chains. The pathophysiology of AIH is complex and involves genetic predisposition, previous exposure to antigens (autoantigens), presence of triggering factors and defects in immunoregulation. In spite of the advances in the understanding of AIH, the role of autoantibodies in the pathophysiology of this disease has not been fully established and their presence does not clearly distinguish any prognostic groups. Further investigations will help in the diagnosis of this disorder, the comprehension of its origins and the establishment of new forms of treatment.

  17. Organophosphorothionate pesticides inhibit the bioactivation of imipramine by human hepatic cytochrome P450s

    Di Consiglio, Emma; Meneguz, Annarita; Testai, Emanuela

    2005-01-01

    The drug-toxicant interaction between the antidepressant imipramine (IMI) and three organophosphorothionate pesticides (OPTs), to which humans may be chronically and simultaneously exposed, has been investigated in vitro. Concentrations of IMI (2-400 μM) and OPTs (≤10 μM) representative of actual human exposure have been tested with recombinant human CYPs and human liver microsomes (HLM). The different CYPs involved in IMI demethylation to the pharmacologically active metabolite desipramine (DES) were CYP2C19 > CYP1A2 > CYP3A4. The OPTs significantly inhibited (up to >80%) IMI bioactivation catalyzed by the recombinant CYPs tested, except CYP2D6, and by HLM; the inhibition was dose-dependent and started at low pesticide concentrations (0.25-2.5 μM). The OPTs, having lower K m values, efficiently competed with IMI for the enzyme active site, as in the case of CYP2C19. However, with CYP1A2 and CYP3A4, a time- and NADPH-dependent mechanism-based inactivation also occurred, consistently with irreversible inhibition due to the release of the sulfur atom, binding to the active CYP during OPT desulfuration. At low IMI and OPT concentrations, lower IC50 values have been obtained with recombinant CYP1A2 (0.7-1.1 μM) or with HLM rich in 1A2-related activity (2-10.8 μM). The K i values (2-14 μM), independent on substrate concentrations, were quite low and similar for the three pesticides. Exposure to OPTs during IMI therapeutic treatments may lead to decreased DES formation, resulting in high plasma levels of the parent drug, eventual impairment of its pharmacological action and possible onset of adverse drug reactions (ADRs)

  18. Mass spectrometry-based proteomic analysis of human liver cytochrome(s) P450

    Shrivas, Kamlesh; Mindaye, Samuel T.; Getie-Kebtie, Melkamu; Alterman, Michail A., E-mail: Michail.Alterman@fda.hhs.gov

    2013-02-15

    The major objective of personalized medicine is to select optimized drug therapies and to a large degree such mission is determined by the expression profiles of cytochrome(s) P450 (CYP). Accordingly, a proteomic case study in personalized medicine is provided by the superfamily of cytochromes P450. Our knowledge about CYP isozyme expression on a protein level is very limited and based exclusively on DNA/mRNA derived data. Such information is not sufficient because transcription and translation events do not lead to correlated levels of expressed proteins. Here we report expression profiles of CYPs in human liver obtained by mass spectrometry (MS)-based proteomic approach. We analyzed 32 samples of human liver microsomes (HLM) of different sexes, ages and ethnicity along with samples of recombinant human CYPs. We have experimentally confirmed that each CYP isozyme can be effectively differentiated by their unique isozyme-specific tryptic peptide(s). Trypsin digestion patterns for almost 30 human CYP isozymes were established. Those findings should assist in selecting tryptic peptides suitable for MS-based quantitation. The data obtained demonstrate remarkable differences in CYP expression profiles. CYP2E1, CYP2C8 and CYP4A11 were the only isozymes found in all HLM samples. Female and pediatric HLM samples revealed much more diverse spectrum of expressed CYPs isozymes compared to male HLM. We have confirmed expression of a number of “rare” CYP (CYP2J2, CYP4B1, CYP4V2, CYP4F3, CYP4F11, CYP8B1, CYP19A1, CYP24A1 and CYP27A1) and obtained first direct experimental data showing expression of such CYPs as CYP2F1, CYP2S1, CYP2W1, CYP4A22, CYP4X1, and CYP26A1 on a protein level. - Highlights: ► First detailed proteomic analysis of CYP isozymes expression in human liver ► Trypsin digestion patterns for almost 30 human CYP isozymes established ► The data obtained demonstrate remarkable differences in CYP expression profiles. ► Female HLM samples revealed more

  19. Mass spectrometry-based proteomic analysis of human liver cytochrome(s) P450

    Shrivas, Kamlesh; Mindaye, Samuel T.; Getie-Kebtie, Melkamu; Alterman, Michail A.

    2013-01-01

    The major objective of personalized medicine is to select optimized drug therapies and to a large degree such mission is determined by the expression profiles of cytochrome(s) P450 (CYP). Accordingly, a proteomic case study in personalized medicine is provided by the superfamily of cytochromes P450. Our knowledge about CYP isozyme expression on a protein level is very limited and based exclusively on DNA/mRNA derived data. Such information is not sufficient because transcription and translation events do not lead to correlated levels of expressed proteins. Here we report expression profiles of CYPs in human liver obtained by mass spectrometry (MS)-based proteomic approach. We analyzed 32 samples of human liver microsomes (HLM) of different sexes, ages and ethnicity along with samples of recombinant human CYPs. We have experimentally confirmed that each CYP isozyme can be effectively differentiated by their unique isozyme-specific tryptic peptide(s). Trypsin digestion patterns for almost 30 human CYP isozymes were established. Those findings should assist in selecting tryptic peptides suitable for MS-based quantitation. The data obtained demonstrate remarkable differences in CYP expression profiles. CYP2E1, CYP2C8 and CYP4A11 were the only isozymes found in all HLM samples. Female and pediatric HLM samples revealed much more diverse spectrum of expressed CYPs isozymes compared to male HLM. We have confirmed expression of a number of “rare” CYP (CYP2J2, CYP4B1, CYP4V2, CYP4F3, CYP4F11, CYP8B1, CYP19A1, CYP24A1 and CYP27A1) and obtained first direct experimental data showing expression of such CYPs as CYP2F1, CYP2S1, CYP2W1, CYP4A22, CYP4X1, and CYP26A1 on a protein level. - Highlights: ► First detailed proteomic analysis of CYP isozymes expression in human liver ► Trypsin digestion patterns for almost 30 human CYP isozymes established ► The data obtained demonstrate remarkable differences in CYP expression profiles. ► Female HLM samples revealed more

  20. Influence of polyhalogenated aromatic hydrocarbons on the induction, activity, and stabilization of cytochrome P450

    Voorman, R.

    1987-01-01

    In the course of experiments evaluating the metabolism of polybrominated biphenyls by cytochrome P450 isozymes induced by 3,4,5,3',4',5'-hexabromobiphenyl (HBB), it was discovered that the inducer remained closely associated with cytochrome P450d. Subsequent purification of cytochromes from HBB treated rates revealed a 0.5:1 association of HBB to cytochrome P450d but virtually none with cytochrome P450c or cytochrome b5. Immunochemical quantitation of cytochrome P450d in the same microsomes yielded a ratio of P450d:HBB that approached unity. Measurement of cytochrome P450d estradiol 2-hydroxylase indicated non-competitive or mixed type inhibition caused by HBB at a concentration of 10-1000 nM. Inhibition was specific to cytochrome P450d since estradiol 2-hydroxylase catalyzed by cytochrome P450h was unaffected by HBB. The ability of HCB and isosafrole to stabilize cytochrome P450d, and thus indirectly influence regulation of the enzyme, was evaluated by treating rats with a dose of TCDD sufficient to produce maximum induction of cytochromes P450c and P450d via the Ah receptor, yet insufficient to bind to the enzyme. Subsequent treatment of these animals with HCB or isosafrole and a radiolabeled amino acid, revealed a significant increase in cytochrome P450d specific content relative to cytochrome P450c and significant retention of the radiolabel in P450d relative to rats treated only with TCDD

  1. Calorimetric studies of the thermal denaturation of cytochrome c peroxidase

    Kresheck, G.C.; Erman, J.E.

    1988-01-01

    Two endotherms are observed by differential scanning calorimetry during the thermal denaturation of cytochrome c peroxidase at pH 7.0. The transition midpoint temperatures (t/sub m/) were 43.9 +- 1.4 and 63.3 +- 1.6 0 C, independent of concentration. The two endotherms were observed at all pH values between 4 and 8, with the transition temperatures varying with pH. Precipitation was observed between pH 4 and 6, and only qualitative data are presented for this region. The thermal unfolding of cytochrome c peroxidase was sensitive to the presence and ligation state of the heme. Only a single endotherm was observed for the unfolding of the apoprotein, and this transition was similar to the high-temperature transition in the holoenzyme. Addition of KCN to the holoenzyme increases the midpoint of the high-temperature transition whereas the low-temperature transition was increased upon addition of KF. Binding of the natural substrate ferricytochrome c to the enzyme increases the low-temperature transition by 4.8 +- 1.3 0 C but has no effect on the high-temperature transition at pH 7. The presence of cytochrome c peroxidase decreases the stability of cytochrome c, and both proteins appear to unfold simultaneously. The results are discussed in terms of the two domains evident in the X-ray crystallographic structure of cytochrome c peroxidase

  2. Oleamide synthesizing activity from rat kidney: identification as cytochrome c.

    Driscoll, William J; Chaturvedi, Shalini; Mueller, Gregory P

    2007-08-03

    Oleamide (cis-9-octadecenamide) is the prototype member of an emerging class of lipid signaling molecules collectively known as the primary fatty acid amides. Current evidence suggests that oleamide participates in the biochemical mechanisms underlying the drive to sleep, thermoregulation, and antinociception. Despite the potential importance of oleamide in these physiologic processes, the biochemical pathway for its synthesis in vivo has not been established. We report here the discovery of an oleamide synthetase found in rat tissues using [(14)C]oleoyl-CoA and ammonium ion. Hydrogen peroxide was subsequently found to be a required cofactor. The enzyme displayed temperature and pH optima in the physiologic range, a remarkable resistance to proteolysis, and specificity for long-chain acyl-CoA substrates. The reaction demonstrated Michaelis-Menten kinetics with a K(m) for oleoyl-CoA of 21 microm. Proteomic, biochemical, and immunologic analyses were used to identify the source of the oleamide synthesizing activity as cytochrome c. This identification was based upon peptide mass fingerprinting of isolated synthase protein, a tight correlation between enzymatic activity and immunoreactivity for cytochrome c, and identical functional properties shared by the tissue-derived synthetase and commercially obtained cytochrome c. The ability of cytochrome c to catalyze the formation of oleamide experimentally raises the possibility that cytochrome c may mediate oleamide biosynthesis in vivo.

  3. Cardiolipin modulates allosterically peroxynitrite detoxification by horse heart cytochrome c

    Ascenzi, Paolo, E-mail: ascenzi@uniroma3.it [Department of Biology and Interdepartmental Laboratory for Electron Microscopy, University Roma Tre, I-00146 Roma (Italy); Ciaccio, Chiara [Department of Experimental Medicine and Biochemical Sciences, University of Roma ' Tor Vergata' , I-00133 Roma (Italy); Interuniversity Consortium for the Research on the Chemistry of Metals in Biological Systems, I-70126 Bari (Italy); Sinibaldi, Federica; Santucci, Roberto [Department of Experimental Medicine and Biochemical Sciences, University of Roma ' Tor Vergata' , I-00133 Roma (Italy); Coletta, Massimo [Department of Experimental Medicine and Biochemical Sciences, University of Roma ' Tor Vergata' , I-00133 Roma (Italy); Interuniversity Consortium for the Research on the Chemistry of Metals in Biological Systems, I-70126 Bari (Italy)

    2011-01-07

    Research highlights: {yields} Cardiolipin binding to cytochrome c. {yields} Cardiolipin-dependent peroxynitrite isomerization by cytochrome c. {yields} Cardiolipin-cytochrome c complex plays pro-apoptotic effects. {yields} Cardiolipin-cytochrome c complex plays anti-apoptotic effects. -- Abstract: Upon interaction with bovine heart cardiolipin (CL), horse heart cytochrome c (cytc) changes its tertiary structure disrupting the heme-Fe-Met80 distal bond, reduces drastically the midpoint potential out of the range required for its physiological role, binds CO and NO with high affinity, and displays peroxidase activity. Here, the effect of CL on peroxynitrite isomerization by ferric cytc (cytc-Fe(III)) is reported. In the absence of CL, hexa-coordinated cytc does not catalyze peroxynitrite isomerization. In contrast, CL facilitates cytc-Fe(III)-mediated isomerization of peroxynitrite in a dose-dependent fashion inducing the penta-coordination of the heme-Fe(III)-atom. The value of the second order rate constant for CL-cytc-Fe(III)-mediated isomerization of peroxynitrite (k{sub on}) is (3.2 {+-} 0.4) x 10{sup 5} M{sup -1} s{sup -1}. The apparent dissociation equilibrium constant for CL binding to cytc-Fe(III) is (5.1 {+-} 0.8) x 10{sup -5} M. These results suggest that CL-cytc could play either pro-apoptotic or anti-apoptotic effects facilitating lipid peroxidation and scavenging of reactive nitrogen species, such as peroxynitrite, respectively.

  4. The antibiotic tiamulin is a potent inducer and inhibitor of cytochrome P4503A via the formation of a stable metabolic intermediate complex. Studies in primary hepatocyte cultures and liver microsomes of the pig.

    Witkamp, R F; Nijmeijer, S M; Monshouwer, M; Van Miert, A S

    1995-05-01

    Tiamulin is a semisynthetic antibiotic frequently used in agricultural animals. The drug has been shown to produce clinically important--often lethal--interactions with other compounds that are simultaneously administered. To explain this, it has been suggested that tiamulin selectively inhibits oxidative drug metabolism via the formation of a cytochrome P450 metabolic intermediate complex. The aim of the present study was to provide further support for this hypothesis. When hepatic microsomes and cultured primary pig hepatocytes were incubated with tiamulin, a maximum in the absorbance spectrum at 455 nm was observed, which disappeared after adding KFe(CN)6. When hepatocytes were incubated with tiamulin for 72 hr, cytochrome P450 content and cytochrome P4503A apoprotein levels were increased. Tiamulin strongly inhibited and concentration dependently inhibited the hydroxylation rate of testosterone at the 6 beta-position in both microsomes and hepatocytes, and the microsomal N-demethylation rate of ethylmorphine. Other testosterone hydroxylations were inhibited to a lesser extent or not affected. The relative inhibition of the hydroxylation of testosterone at the 6 beta-position was more pronounced in microsomes from rifampicin- and triacetyloleandomycin-treated pigs. The results indicate that cytochrome P450 complex formation can at least partly explain the interactions observed with tiamulin. Tiamulin seems to be a strong, probably selective, inhibitor of the cytochrome P4503A subfamily and an interesting tool for further research.

  5. The hepatic bridge.

    Sugarbaker, Paul H

    2018-07-01

    The hepatic bridge forms a tunnel of liver parenchyma that may obscure peritoneal metastases associated with the round ligament. Visualization and then resection of nodules associated with this structure is necessary. The incidence of a hepatic bridge and the extent that it covered the round ligament was determined in consecutive patients. Extent of coverage of the round ligament by the hepatic bridge was determined: Class 1 indicates up to one-third of the round ligament obscured, Class 2 up to two-thirds and Class 3 more than two-thirds. In 102 patients in whom the round ligament of the liver could be completely visualized, 50 had a hepatic bridge. Class 1 was 22 (44%) of the bridges, Class 2 was 16 (32%) and Class 3 was 12 (24%). A hepatic bridge was more frequently present in 28 of 45 male patients (62%) vs. 22 of 57 female patients (38%). Approximately one-half of our patients having cytoreductive surgery for peritoneal metastases were observed to have a hepatic bridge. Up to 56% of these patients have Class 2 or 3 hepatic bridge and may require division of the hepatic bridge to completely visualize the contents of the tunnel created by this structure. Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

  6. Hepatitis C Test

    ... and Prevention. Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945–1965. Prepared by ... Disease Control and Prevention. Vital Signs: Evaluation of Hepatitis C Virus Infection Testing and Reporting — Eight U.S. Sites, 2005–2011. ...

  7. [History of viral hepatitis].

    Fonseca, José Carlos Ferraz da

    2010-01-01

    The history of viral hepatitis goes back thousands of years and is a fascinating one. When humans were first infected by such agents, a natural repetitive cycle began, with the capacity to infect billions of humans, thus decimating the population and causing sequelae in thousands of lives. This article reviews the available scientific information on the history of viral hepatitis. All the information was obtained through extensive bibliographic review, including original and review articles and consultations on the internet. There are reports on outbreaks of jaundice epidemics in China 5,000 years ago and in Babylon more than 2,500 years ago. The catastrophic history of great jaundice epidemics and pandemics is well known and generally associated with major wars. In the American Civil War, 40,000 cases occurred among Union troops. In 1885, an outbreak of catarrhal jaundice affected 191 workers at the Bremen shipyard (Germany) after vaccination against smallpox. In 1942, 28,585 soldiers became infected with hepatitis after inoculation with the yellow fever vaccine. The number of cases of hepatitis during the Second World War was estimated to be 16 million. Only in the twentieth century were the main agents causing viral hepatitis identified. The hepatitis B virus was the first to be discovered. In this paper, through reviewing the history of major epidemics caused by hepatitis viruses and the history of discovery of these agents, singular peculiarities were revealed. Examples of this include the accidental or chance discovery of the hepatitis B and D viruses.

  8. Cytomegalovirus Hepatitis During Pregnancy

    Ying Chan

    1995-01-01

    Full Text Available Background: Although cytomegalovirus (CMV is an uncommon cause of viral hepatitis during pregnancy, a definitive diagnosis is important because of the potential for congenital CMV. In the case reported here, a diagnosis of hepatitis caused by CMV was made after the more common viral pathogens had been ruled out.

  9. Hepatitis E og graviditet

    Mannheimer, Ebba Elisabeth; Harritshøj, Lene Holm; Katzenstein, Terese Lea

    2016-01-01

    Hepatitis E virus (HEV) infection among pregnant women is severe, often leading to fulminant hepatic failure and death, with mortality rates up to 15-25%. Studies suggest that differences in genotypes/subgenotypes, hormonal and immunological changes during pregnancy may contribute to the severe...

  10. Pentoxifylline for alcoholic hepatitis

    Whitfield, Kate; Rambaldi, Andrea; Wetterslev, Jørn

    2009-01-01

    BACKGROUND: Alcoholic hepatitis is a life-threatening disease, with an average mortality of approximately 40%. There is no widely accepted, effective treatment for alcoholic hepatitis. Pentoxifylline is used to treat alcoholic hepatitis, but there has been no systematic review to assess its effects....... OBJECTIVES: To assess the benefits and harms of pentoxifylline in alcoholic hepatitis. SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS......, clinicaltrials.gov, and full text searches were conducted until August 2009. Manufacturers and authors were contacted. SELECTION CRITERIA: All randomised clinical trials of pentoxifylline in participants with alcoholic hepatitis compared to control were selected for inclusion. DATA COLLECTION AND ANALYSIS: Two...

  11. Serum Hepatitis C virus and hepatitis B surface antigenaemia in ...

    Acute hepatitis is common in Nigeria and hepatitis B virus (HBV) infection has been a major aetiological factor. However, the role of Hepatitis C virus (HCV) infection is yet undetermined. Forty-five consecutive Nigerian patients with acute Icteric hepatitis (AIH) attending the Medical Clinic of the University College Hospital, ...

  12. Mitochondrial cytochrome c biogenesis: no longer an enigma.

    Babbitt, Shalon E; Sutherland, Molly C; San Francisco, Brian; Mendez, Deanna L; Kranz, Robert G

    2015-08-01

    Cytochromes c (cyt c) and c1 are heme proteins that are essential for aerobic respiration. Release of cyt c from mitochondria is an important signal in apoptosis initiation. Biogenesis of c-type cytochromes involves covalent attachment of heme to two cysteines (at a conserved CXXCH sequence) in the apocytochrome. Heme attachment is catalyzed in most mitochondria by holocytochrome c synthase (HCCS), which is also necessary for the import of apocytochrome c (apocyt c). Thus, HCCS affects cellular levels of cyt c, impacting mitochondrial physiology and cell death. Here, we review the mechanisms of HCCS function and the roles of heme and residues in the CXXCH motif. Additionally, we consider concepts emerging within the two prokaryotic cytochrome c biogenesis pathways. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Cytochrome c catalyzes the in vitro synthesis of arachidonoyl glycine

    McCue, Jeffrey M.; Driscoll, William J.; Mueller, Gregory P.

    2008-01-01

    Long chain fatty acyl glycines are an emerging class of biologically active molecules that occur naturally and produce a wide array of physiological effects. Their biosynthetic pathway, however, remains unknown. Here we report that cytochrome c catalyzes the synthesis of N-arachidonoyl glycine (NAGly) from arachidonoyl coenzyme A and glycine in the presence of hydrogen peroxide. The identity of the NAGly product was verified by isotope labeling and mass analysis. Other heme-containing proteins, hemoglobin and myoglobin, were considerably less effective in generating arachidonoyl glycine as compared to cytochrome c. The reaction catalyzed by cytochrome c in vitro points to its potential role in the formation of NAGly and other long chain fatty acyl glycines in vivo

  14. Fast prediction of cytochrome P450 mediated drug metabolism

    Rydberg, Patrik Åke Anders; Poongavanam, Vasanthanathan; Oostenbrink, Chris

    2009-01-01

    Cytochrome P450 mediated metabolism of drugs is one of the major determinants of their kinetic profile, and prediction of this metabolism is therefore highly relevant during the drug discovery and development process. A new rule-based method, based on results from density functional theory...... calculations, for predicting activation energies for aliphatic and aromatic oxidations by cytochromes P450 is developed and compared with several other methods. Although the applicability of the method is currently limited to a subset of P450 reactions, these reactions describe more than 90...

  15. Evaluation of cytochrome P-450 concentration in Saccharomyces cerevisiae strains

    Míriam Cristina Sakuragui Matuo

    2010-09-01

    Full Text Available Saccharomyces cerevisiae has been widely used in mutagenicity tests due to the presence of a cytochrome P-450 system, capable of metabolizing promutagens to active mutagens. There are a large number of S. cerevisiae strains with varying abilities to produce cytochrome P-450. However, strain selection and ideal cultivation conditions are not well defined. We compared cytochrome P-450 levels in four different S. cerevisiae strains and evaluated the cultivation conditions necessary to obtain the highest levels. The amount of cytochrome P-450 produced by each strain varied, as did the incubation time needed to reach the maximum level. The highest cytochrome P-450 concentrations were found in media containing fermentable sugars. The NCYC 240 strain produced the highest level of cytochrome P-450 when grown in the presence of 20 % (w/v glucose. The addition of ethanol to the media also increased cytochrome P-450 synthesis in this strain. These results indicate cultivation conditions must be specific and well-established for the strain selected in order to assure high cytochrome P-450 levels and reliable mutagenicity results.Linhagens de Saccharomyces cerevisiae tem sido amplamente empregadas em testes de mutagenicidade devido à presença de um sistema citocromo P-450 capaz de metabolizar substâncias pró-mutagênicas à sua forma ativa. Devido à grande variedade de linhagens de S. cerevisiae com diferentes capacidades de produção de citocromo P-450, torna-se necessária a seleção de cepas, bem como a definição das condições ideais de cultivo. Neste trabalho, foram comparados os níveis de citocromo P-450 em quatro diferentes linhagens de S. cerevisiae e avaliadas as condições de cultivo necessárias para obtenção de altas concentrações deste sistema enzimático. O maior nível enzimático foi encontrado na linhagem NCYC 240 em presença de 20 % de glicose (p/v. A adição de etanol ao meio de cultura também produziu um aumento na s

  16. Dopaminergic agonists for hepatic encephalopathy

    Als-Nielsen, B; Gluud, L L; Gluud, C

    2004-01-01

    Hepatic encephalopathy may be associated with an impairment of the dopaminergic neurotransmission. Dopaminergic agonists may therefore have a beneficial effect on patients with hepatic encephalopathy.......Hepatic encephalopathy may be associated with an impairment of the dopaminergic neurotransmission. Dopaminergic agonists may therefore have a beneficial effect on patients with hepatic encephalopathy....

  17. Normal variation of hepatic artery

    Kim, Inn; Nam, Myung Hyun; Rhim, Hyun Chul; Koh, Byung Hee; Seo, Heung Suk; Kim, Soon Yong

    1987-01-01

    This study was an analyses of blood supply of the liver in 125 patients who received hepatic arteriography and abdominal aortography from Jan. 1984 to Dec. 1986 at the Department of Radiology of Hanyang University Hospital. A. Variations in extrahepatic arteries: 1. The normal extrahepatic artery pattern occurred in 106 of 125 cases (84.8%) ; Right hepatic and left hepatic arteries arising from the hepatic artery proper and hepatic artery proper arising from the common hepatic artery. 2. The most common type of variation of extrahepatic artery was replaced right hepatic artery from superior mesenteric artery: 6 of 125 cases (4.8%). B. Variations in intrahepatic arteries: 1. The normal intrahepatic artery pattern occurred in 83 of 125 cases (66.4%). Right hepatic and left hepatic arteries arising from the hepatic artery proper and middle hepatic artery arising from lower portion of the umbilical point of left hepatic artery. 2. The most common variation of intrahepatic arteries was middle hepatic artery. 3. Among the variation of middle hepatic artery; Right, middle and left hepatic arteries arising from the same location at the hepatic artery proper was the most common type; 17 of 125 cases (13.6%)

  18. Glucocorticosteroids for viral hepatitis C

    Brok, J; Mellerup, M T; Krogsgaard, K

    2004-01-01

    Hepatitis C virus may cause liver inflammation and fibrosis. It is not known whether glucocorticosteroids are beneficial or harmful for patients with hepatitis C infection.......Hepatitis C virus may cause liver inflammation and fibrosis. It is not known whether glucocorticosteroids are beneficial or harmful for patients with hepatitis C infection....

  19. Cytochrome P450 regulation: the interplay between its heme and apoprotein moieties in synthesis, assembly, repair, and disposal.

    Correia, Maria Almira; Sinclair, Peter R; De Matteis, Francesco

    2011-02-01

    Heme is vital to our aerobic universe. Heme cellular content is finely tuned through an exquisite control of synthesis and degradation. Heme deficiency is deleterious to cells, whereas excess heme is toxic. Most of the cellular heme serves as the prosthetic moiety of functionally diverse hemoproteins, including cytochromes P450 (P450s). In the liver, P450s are its major consumers, with >50% of hepatic heme committed to their synthesis. Prosthetic heme is the sine qua non of P450 catalytic biotransformation of both endo- and xenobiotics. This well-recognized functional role notwithstanding, heme also regulates P450 protein synthesis, assembly, repair, and disposal. These less well-appreciated aspects are reviewed herein.

  20. Curcumin Prevents Aflatoxin B1 Hepatoxicity by Inhibition of Cytochrome P450 Isozymes in Chick Liver

    Ni-Ya Zhang

    2016-11-01

    Full Text Available This study was designed to establish if Curcumin (CM alleviates Aflatoxin B1 (AFB1-induced hepatotoxic effects and to determine whether alteration of the expression of cytochrome P450 (CYP450 isozymes is involved in the regulation of these effects in chick liver. One-day-old male broilers (n = 120 were divided into four groups and used in a two by two factorial trial in which the main factors included supplementing AFB1 (< 5 vs. 100 μg/kg and CM (0 vs. 150 mg/kg in a corn/soybean-based diet. Administration of AFB1 induced liver injury, significantly decreasing albumin and total protein concentrations and increasing alanine aminotransferase and aspartate aminotransferase activities in serum, and induced hepatic histological lesions at week 2. AFB1 also significantly decreased hepatic glutathione peroxidase, catalase, and glutathione levels, while increasing malondialdehyde, 8-hydroxydeoxyguanosine, and exo-AFB1-8,9-epoxide (AFBO-DNA concentrations. In addition, the mRNA and/or activity of enzymes responsible for the bioactivation of AFB1 into AFBO—including CYP1A1, CYP1A2, CYP2A6, and CYP3A4—were significantly induced in liver microsomes after 2-week exposure to AFB1. These alterations induced by AFB1 were prevented by CM supplementation. Conclusively, dietary CM protected chicks from AFB1-induced liver injury, potentially through the synergistic actions of increased antioxidant capacities and inhibition of the pivotal CYP450 isozyme-mediated activation of AFB1 to toxic AFBO.

  1. Metabolism of ethylbenzene by human liver microsomes and recombinant human cytochrome P450s (CYP).

    Sams, Craig; Loizou, George D; Cocker, John; Lennard, Martin S

    2004-03-07

    The enzyme kinetics of the initial hydroxylation of ethylbenzene to form 1-phenylethanol were determined in human liver microsomes. The individual cytochrome P450 (CYP) forms catalysing this reaction were identified using selective inhibitors and recombinant preparations of hepatic CYPs. Production of 1-phenylethanol in hepatic microsomes exhibited biphasic kinetics with a high affinity, low Km, component (mean Km = 8 microM; V(max) = 689 pmol/min/mg protein; n = 6 livers) and a low affinity, high Km, component (Km = 391 microM; V(max) = 3039 pmol/min/mg protein; n = 6). The high-affinity component was inhibited 79%-95% (mean 86%) by diethyldithiocarbamate, and recombinant CYP2E1 was shown to metabolise ethylbenzene with low Km (35 microM), but also low (max) (7 pmol/min/pmol P450), indicating that this isoform catalysed the high-affinity component. Recombinant CYP1A2 and CYP2B6 exhibited high V(max) (88 and 71 pmol/min/pmol P450, respectively) and high Km (502 and 219 microM, respectively), suggesting their involvement in catalysing the low-affinity component. This study has demonstrated that CYP2E1 is the major enzyme responsible for high-affinity side chain hydroxylation of ethylbenzene in human liver microsomes. Activity of this enzyme in the population is highly variable due to induction or inhibition by physiological factors, chemicals in the diet or some pharmaceuticals. This variability can be incorporated into the risk assessment process to improve the setting of occupational exposure limits and guidance values for biological monitoring.

  2. Induced cytochrome P450 1A activity in cichlid fishes from Guandu River and Jacarepagua Lake, Rio de Janeiro, Brazil

    Parente, Thiago E.M.; Oliveira, Ana C.A.X. de; Paumgartten, Francisco J.R.

    2008-01-01

    The induction of cytochrome P4501A-mediated activity (e.g. ethoxyresorufin-O-deethylation, EROD) has been used as a biomarker for monitoring fish exposure to AhR-receptor ligands such as polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB) and polychlorinated dibenzo-dioxins/furans (PCDD/Fs). In this study we found that hepatic EROD is induced in fish ('Nile tilapia', Oreochromis niloticus and 'acara', Geophagus brasiliensis) from the Guandu River (7-17-fold) and Jacarepagua Lake (7-fold), Rio de Janeiro, Brazil. Since both cichlid fish are consumed by the local population and the Guandu River is the main source of the drinking water supply for the greater Rio de Janeiro metropolitan area, pollution by cytochrome P4501A-inducing chemicals is a cause for concern and should be further investigated in sediments, water and biota. We additionally showed that EROD activity in the fish liver post-mitochondrial supernatant-simpler, cheaper and less time consuming to prepare than the microsomal fraction-is sufficiently sensitive for monitoring purposes. - Increased EROD activity in the liver of cichlid fishes indicated that Guandu River, the source of drinking water supply for Rio de Janeiro is polluted by CYP1A-inducing chemicals

  3. Induced cytochrome P450 1A activity in cichlid fishes from Guandu River and Jacarepagua Lake, Rio de Janeiro, Brazil

    Parente, Thiago E.M.; Oliveira, Ana C.A.X. de [Laboratorio de Toxicologia Ambiental, Escola Nacional de Saude Publica - FIOCRUZ, Av Brasil 4036, Predio de Expansao do Campus, Rio de Janeiro, RJ 21041-361 (Brazil); Paumgartten, Francisco J.R. [Laboratorio de Toxicologia Ambiental, Escola Nacional de Saude Publica - FIOCRUZ, Av Brasil 4036, Predio de Expansao do Campus, Rio de Janeiro, RJ 21041-361 (Brazil)], E-mail: paum@ensp.fiocruz.br

    2008-03-15

    The induction of cytochrome P4501A-mediated activity (e.g. ethoxyresorufin-O-deethylation, EROD) has been used as a biomarker for monitoring fish exposure to AhR-receptor ligands such as polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB) and polychlorinated dibenzo-dioxins/furans (PCDD/Fs). In this study we found that hepatic EROD is induced in fish ('Nile tilapia', Oreochromis niloticus and 'acara', Geophagus brasiliensis) from the Guandu River (7-17-fold) and Jacarepagua Lake (7-fold), Rio de Janeiro, Brazil. Since both cichlid fish are consumed by the local population and the Guandu River is the main source of the drinking water supply for the greater Rio de Janeiro metropolitan area, pollution by cytochrome P4501A-inducing chemicals is a cause for concern and should be further investigated in sediments, water and biota. We additionally showed that EROD activity in the fish liver post-mitochondrial supernatant-simpler, cheaper and less time consuming to prepare than the microsomal fraction-is sufficiently sensitive for monitoring purposes. - Increased EROD activity in the liver of cichlid fishes indicated that Guandu River, the source of drinking water supply for Rio de Janeiro is polluted by CYP1A-inducing chemicals.

  4. Feline Hepatic Lipidosis.

    Valtolina, Chiara; Favier, Robert P

    2017-05-01

    Feline hepatic lipidosis (FHL) is a common and potentially fatal liver disorder. Although the pathophysiologic mechanisms of FHL remain elusive, there is an imbalance between the influx of fatty acids from peripheral fat stores into the liver, de novo liposynthesis, and the rate of hepatic oxidation and dispersal of hepatic TAG via excretion of very-low density lipoproteins. The diagnosis of FHL is based on anamnestic, clinical, and clinicopathologic findings, associated with diagnostic imaging of the liver, and cytology, or histological examination of liver biopsies. Fluid therapy, electrolyte correction and adequate early nutrition are essential components of the therapy for FHL. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Effect of carbon source on the accumulation of cytochrome P-450 in the yeast Saccharomyces cerevisiae.

    Kärenlampi, S O; Marin, E; Hänninen, O O

    1981-01-01

    The appearance of cytochrome P-450 in the yeast Saccharomyces cerevisiae depended on the substrate supporting growth. Cytochrome P-450 was apparent in yeast cells grown on a strongly fermentable sugar such as D-glucose, D-fructose or sucrose. When yeast was grown on D-galactose, D-mannose or maltose, where fermentation and respiration occurred concomitantly, cytochrome P-450 was also formed. The cytochrome P-450 concentration was maximal at the beginning of the stationary phase of the culture...

  6. Effect of isolated hepatic ischemia on organic anion clearance and oxidative metabolism.

    Minard, G; Bynoe, R; Wood, G C; Fabian, T C; Croce, M; Kudsk, K A

    1992-04-01

    Hepatic failure is frequently seen following severe hemorrhagic shock, sepsis, and trauma. Clearance of various drugs has been used to evaluate hepatocellular dysfunction, including indocyanine green (ICG), an organic anionic dye that is transported similarly to bilirubin, and antipyrine (AP), a marker of oxidative phosphorylation. Previous investigators have noted a decrease in ICG excretion following systemic hemorrhage. The effect of isolated hepatic ischemia on the clearances of ICG and AP was studied in 16 pigs after 90 minutes of vascular occlusion to the liver. Antipyrine clearance decreased almost 50% from baseline values at 24 and 72 hours after the ischemia procedure, indicating a significant depression in the cytochrome P-450 system. On the other hand, ICG clearance did not change significantly. In conclusion, ICG clearance is not depressed after isolated hepatic ischemia in pigs. Changes in organic anion clearance after systemic hemorrhage may be because of release of toxic products from ischemic peripheral tissue.

  7. Computational identification of putative cytochrome P450 genes in ...

    Chattha

    Economically, legumes represent the second most important family of crop plants after Poacea (grass family), accounting for ... further characterization of P450 genes with both known and unknown functions. MATERIALS AND METHODS ..... Cytochrome P450. In: Somerville CR, Meyerowitz EM (eds) .The Arabidopsis book,.

  8. Interplay between cytochrome c and gibberellins during Arabidopsis vegetative development

    Racca, S.; Welchen, E.; Gras, D. E.; Tarkowská, Danuše; Turečková, Veronika; Maurino, V. G.; Gonzalez, D. H.

    2018-01-01

    Roč. 94, č. 1 (2018), s. 105-121 ISSN 0960-7412 R&D Projects: GA MŠk(CZ) LO1204 Institutional support: RVO:61389030 Keywords : Arabidopsis thaliana * cytochrome c * DELLA protein * gibberellin * mitochondrion Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Plant sciences, botany Impact factor: 5.901, year: 2016

  9. Redox Thermodynamics of Cytochromes c Subjected to Urea Induced Unfolding

    Monari, S.; Ranieri, A.; Di Rocco, G.; van der Zwan, G.; Peressini, S.; Tavagnacco, C.; Millo, D.; Borsari, M.

    2009-01-01

    The thermodynamics of the electron transfer (ET) process for beef heart and yeast cytochromes c and the Lys72Ala/Lys73Ala/Lys79Ala mutant of the latter species subjected to progressive urea-induced unfolding was determined electrochemically. The results indicate the presence of at least three

  10. Multivariate Modeling of Cytochrome P450 Enzymes for 4 ...

    Conclusion: Apart from insights into important molecular properties for CYP inhibition, the findings may also guide further investigations of novel drug candidates that are unlikely to inhibit multiple CYP sub-types. Keywords: Antimalarial, Chloroquine, Cytochrome P450, Genetic algorithm-based multiple linear regression, ...

  11. Feature Hepatitis: The Dangers of Hepatitis: What you should know from A to E

    ... Navigation Bar Home Current Issue Past Issues Feature Hepatitis The Dangers of Hepatitis: What you should know from A to E ... drugs. In some cases, hepatitis lasts a lifetime. Hepatitis: Acute or Chronic? Acute hepatitis is the initial ...

  12. Sex difference in the principal cytochrome P-450 for tributyltin metabolism in rats

    Ohhira, Shuji; Enomoto, Mitsunori; Matsui, Hisao

    2006-01-01

    Tributyltin is metabolized by cytochrome P-450 (CYP) system enzymes, and its metabolic fate may contribute to the toxicity of the chemical. In the present study, it is examined whether sex differences in the metabolism of tributyltin exist in rats. In addition, the in vivo and in vitro metabolism of tributyltin was investigated using rat hepatic CYP systems to confirm the principal CYP involved. A significant sex difference in metabolism occurred both in vivo and in vitro, suggesting that one of the CYPs responsible for tributyltin metabolism in rats is male specific or predominant at least. Eight cDNA-expressed rat CYPs, including typical phenobarbital (PB)-inducible forms and members of the CYP2C subfamily, were tested to determine their capability for tributyltin metabolism. Among the enzymes studied, a statistically significant dealkylation of tributyltin was mediated by CYP2C6 and 2C11. Furthermore, the sex difference in metabolism disappeared in vitro after anti-rat CYP2C11 antibody pretreatment because CYP2C11 is a major male-specific form in rats. These results indicate that CYP2C6 is the principal CYP for tributyltin metabolism in female rats, whereas CYP2C11 as well as 2C6 is involved in tributyltin metabolism in male rats, and it is suggested that CYP2C11 is responsible for the significant sex difference in the metabolism of tributyltin observed in rats

  13. HIV and Hepatitis C

    ... AIDS Drugs Clinical Trials Apps skip to content HIV and Opportunistic Infections, Coinfections, and Conditions Home Understanding ... 4 p.m. ET) Send us an email HIV and Hepatitis C Last Reviewed: July 25, 2017 ...

  14. HIV and Hepatitis B

    ... AIDS Drugs Clinical Trials Apps skip to content HIV and Opportunistic Infections, Coinfections, and Conditions Home Understanding ... 4 p.m. ET) Send us an email HIV and Hepatitis B Last Reviewed: July 24, 2017 ...

  15. Imaging of hepatic infections

    Doyle, D.J.; Hanbidge, A.E.; O'Malley, M.E.

    2006-01-01

    Imaging plays a significant role in the detection, characterization and treatment of hepatic infections. Infectious diseases of the liver include pyogenic and amoebic abscesses and parasitic, fungal, viral and granulomatous infections. With increases in worldwide travel, immunosuppression and changing population demographics, identification of cases of hepatic infection is becoming more common in daily practice. Knowledge of the imaging features seen with hepatic infections can assist in early diagnosis and timely initiation of appropriate therapy. This review presents the imaging appearances of hepatic infections, emphasizing specific features that may contribute to the diagnosis. Examples of the imaging findings seen with pyogenic and amoebic abscesses, infection with Echinococcus granulosus (Hydatid), schistosomiasis, candidiasis and tuberculosis (TB) are presented

  16. Imaging of hepatic infections

    Doyle, D.J. [Department of Medical Imaging, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, Ont. (Canada)]. E-mail: doyledj@hotmail.com; Hanbidge, A.E. [Department of Medical Imaging, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, Ont. (Canada); O' Malley, M.E. [Department of Medical Imaging, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, Ont. (Canada)

    2006-09-15

    Imaging plays a significant role in the detection, characterization and treatment of hepatic infections. Infectious diseases of the liver include pyogenic and amoebic abscesses and parasitic, fungal, viral and granulomatous infections. With increases in worldwide travel, immunosuppression and changing population demographics, identification of cases of hepatic infection is becoming more common in daily practice. Knowledge of the imaging features seen with hepatic infections can assist in early diagnosis and timely initiation of appropriate therapy. This review presents the imaging appearances of hepatic infections, emphasizing specific features that may contribute to the diagnosis. Examples of the imaging findings seen with pyogenic and amoebic abscesses, infection with Echinococcus granulosus (Hydatid), schistosomiasis, candidiasis and tuberculosis (TB) are presented.

  17. hy viral hepatitis?

    jelivery.6 They may be confused with surgical conditions and apart from being an ... of the viruses, the diagnosis and treatment of chronic hepatitis, the relationship of .... myocarditis and cardiomyopathy, pancreatitis and CSF abnormalities!

  18. Autoantibodies in Autoimmune Hepatitis.

    Muratori, Luigi; Deleonardi, Gaia; Lalanne, Claudine; Barbato, Erica; Tovoli, Alessandra; Libra, Alessia; Lenzi, Marco; Cassani, Fabio; Muratori, Paolo

    2015-01-01

    The detection of diagnostic autoantibodies such as antinuclear antibodies (ANA), anti-smooth muscle antibodies (SMA), anti-liver/kidney microsomal type 1 (anti-LKM1), anti-liver cytosol type 1 (anti-LC1) and anti-soluble liver antigen (anti-SLA) is historically associated with the diagnosis of autoimmune hepatitis. When autoimmune hepatitis is suspected, the detection of one or any combination of diagnostic autoantibodies, by indirect immunofluorescence or immuno-enzymatic techniques with recombinant antigens, is a pivotal step to reach a diagnostic score of probable or definite autoimmune hepatitis. Diagnostic autoantibodies (ANA, SMA, anti-LKM1, anti-LC1, anti-SLA) are a cornerstone in the diagnosis of autoimmune hepatitis. Other ancillary autoantibodies, associated with peculiar clinical correlations, appear to be assay-dependent and institution-specific, and validation studies are needed. © 2015 S. Karger AG, Basel.

  19. Hepatic abscesses after adhesiolysis

    J. Antonsen

    2015-01-01

    Conclusion: Febrilia and pain in upper right quadrant of the abdomen days after a simple operation for bowel obstruction could be caused by translocation of intestinal bacteria and subsequent formation of hepatic abscesses.

  20. Hepatitis C pada Anak

    Yusri Dianne Jurnalis

    2014-05-01

    Full Text Available AbstrakInfeksi virus hepatitis C saat ini masih merupakan persoalan yang serius. Penularan infeksi HCV pada anak yang utama adalah melalui transfusi darah atau produk darah yang saat ini bertanggung jawab menyebabkan kasus hepatitis C kronis. Selain itu infeksi HCV pada anak dapat disebabkan oleh transmisi perinatal (vertikal. Infeksi HCV akut dapat berakhir dengan sirosis dan karsinoma hepatoselular setelah dekade ketiga (sekitar 20%, karena progresivitas infeksi HCV lebih lambat dari infeksi hepatitis B virus. Pada umumnya infeksi HCV bersifat asimptomatik termasuk pada anak. Karena tidak ada gejala yang jelas pada infeksi HCV tersebut maka diagnosis infeksi HCV hanya dapat ditegakkan dengan pemeriksaan awal laboratorium dan uji serologi, dan bila perlu dengan uji molekuler pada pasien dengan risiko tinggi. Kebijakan kuratif khusus terhadap HCV adalah terapi antivirus berupa interferon dan ribavirin yang diberikan bila diagnosis HCV sudah ditegakkanKata kunci: Hepatitis C, diagnosis and management problem, childrenAbstractHepatitis C virus infection is still a serious problem. Transmission of HCV infection in children is a major blood transfusion or blood products that are currently responsible for causing chronic hepatitis C cases. Additionally HCV infection in children can be caused by perinatal transmission (vertical. Acute HCV infection may end up with cirrhosis and hepatocellular carcinoma after the third decade (around 20%, due to a slower progression of HCV infection of hepatitis B virus infection. In most cases of HCV infection are asymptomatic, including in children. Since there are no obvious symptoms in the diagnosis of HCV infection HCV infection can only be confirmed by laboratory examinations and serologic testing early, and if necessary with molecular testing in patients at high risk. Curative policy is specific to HCV antiviral therapy such as interferon and ribavirin are given when the diagnosis of HCV has been establishedKeywords:Hepatitis

  1. Crioglobulinemia y hepatitis

    Rousseau González, Georgina

    1998-01-01

    Se describieron las manifestaciones principales de la crioglobulinemia mixta esencial su clasificación inmunoquímica, su asociación con los distintos virus de la hepatitis, las distintas alteraciones inmunológicas asociadas y los principales tratamientos utilizados. The main manifestations of essential mixed cryoglobulinemia were described: its immunochemical classification, its association with different hepatitis virus, the different associated immunological alterations, and the main tre...

  2. Hepatic rupture in preeclampsia

    Winer-Muram, H.T.; Muram, D.; Salazar, J.; Massie, J.D.

    1985-01-01

    The diagnosis of hepatic rupture in patients with pregnancy-induced hypertension (preeclampsia and eclampsia) is rarely made preoperatively. Diagnostic imaging can be utilized in some patients to confirm the preoperative diagnosis. Since hematoma formation precedes hepatic rupture, then, when diagnostic modalities such as sonography and computed tomography identify patients with hematomas, these patients are at risk of rupture, and should be hospitalized until the hematomas resolve

  3. Torsed pedunculated hepatic hamartoma

    Vazquez-Lima, Ignacio; Vazquez, Jose L.; Gallego, Marta; Fernandez, Rebeca; Fernandez, Pilar

    2009-01-01

    We report a 9-year-old boy with a 6-h history of acute abdominal pain due to torsion of a pedunculated hepatic mesenchymal hamartoma. The lesion was seen, on US and CT, to connect to the liver through a pedicle. Mesenchymal hepatic hamartomas are unusual tumours that may be pedunculated, and this is a unique case complicated by torsion. The radiological and pathological findings, differential diagnosis, and clinical course are discussed. (orig.)

  4. FELINE HEPATIC LIPIDOSIS

    C. Masotti; M. O. Lima; A. M. Cruz; G. D. Cruz

    2016-01-01

    Since the first description of feline hepatic lipidosis occurred in 1977, it becames the most diagnosed liver disease in cats. Several factors have been proposed as causes of disease, and obesity being a predisposing factor. The disease can be considered primary or idiopathic when its underlying cause is unknown, or secondary when there is another concomitant disease lipidosis. Cats with hepatic lipidosis have anorexia usually ranging from several days to weeks and weight loss, followed by ja...

  5. CT in hepatic abscess

    Fujita, Nobuyuki; Hiromura, Tadao; Saitoh, Hiroya; Choji, Kiyoshi; Takahashi, Hiromichi; Shinohara, Masahiro; Irie, Goroh; Nojima, Takayuki; Morita, Yuzuru.

    1987-01-01

    Fifteen CT pictures from 10 cases of hepatic abscess were reviewed. Rim enhancement was noted only in 2. On the other hand, ill defined low density surrounding central cystic structure was demonstrated in 11. Following contrast injection, this ill defined low density becomes isodense to the normal liver. Histologically, the ill defined low density was granulation tissue composed of neutrophils, lymphocytes and Macrophages. We emphasized the importance of the recognition of the granulation tissue surraounding a cyst of hepatic abscess. (author)

  6. Hepatitis C in dermatology

    Zonunsanga

    2015-10-01

    Full Text Available Hepatitis C is a serious public health problem all over the world. It is caused by a single stranded RNA virus. Most acute infections are subclinical, but in 75% of individuals, infection leads to a chronic hepatitis, which in some cases can progress to cirrhosis and occasionally development of hepatoma. It has wide range of dermatological manifestations. This review article deals with the overview of epidemiology, pathogenesis, clinical manifestations, management and prevention.

  7. A novel assay for detecting antibodies to cytochrome P4502D6, the molecular target of liver kidney microsomal antibody type 1.

    Kerkar, N; Ma, Y; Hussain, M; Muratori, L; Targett, C; Williams, R; Bianchi, F B; Mieli-Vergani, G; Vergani, D

    1999-03-04

    Liver Kidney Microsomal type 1 (LKM1) antibody, the diagnostic marker of autoimmune hepatitis type 2, is also found in a proportion of patients with hepatitis C virus infection (HCV). It is detected conventionally by the subjective immunofluorescence technique. Our aim was to establish a simple and objective enzyme-linked immunosorbent assay (ELISA) that measures antibodies to cytochrome P4502D6 (CYP2D6), the target of LKM1. An indirect ELISA using eukaryotically expressed CYP2D6 was designed. Absorbance values obtained against a reference microsomal preparation were subtracted from those obtained against a microsomal preparation over-expressing CYP2D6, thus removing the non-CYP2D6-specific reaction. Sera from 51 LKM1 positive patients (21 autoimmune hepatitis and 30 with HCV infection), 111 LKM1 negative patients with chronic liver disease (including 20 with HCV infection) and 43 healthy controls were tested. Of 51 patients positive by immunofluorescence, 48 were also positive by ELISA while all the 154 LKM1 negative subjects were also negative by ELISA. There was a high degree of association between IFL and ELISA as demonstrated by a kappa reliability value of 0.96. The absorbance values by ELISA correlated with immunofluorescence LKM1 titres both in autoimmune hepatitis (r = 0.74, p < 0.001) and HCV infection (r = 0.67, p < 0.001). The simple, objective ELISA described has the potential to replace the standard immunofluorescence technique.

  8. FELINE HEPATIC LIPIDOSIS

    C. Masotti

    2016-11-01

    Full Text Available Since the first description of feline hepatic lipidosis occurred in 1977, it becames the most diagnosed liver disease in cats. Several factors have been proposed as causes of disease, and obesity being a predisposing factor. The disease can be considered primary or idiopathic when its underlying cause is unknown, or secondary when there is another concomitant disease lipidosis. Cats with hepatic lipidosis have anorexia usually ranging from several days to weeks and weight loss, followed by jaundice and varying degrees of dehydration, diarrhea and vomiting episodes may occur. A worsening of the disease shows signs of hepatic encephalopathy, drooling and retroflexion of the neck. In clinical examination can be observed depression, lethargy and hepatomegaly. The definitive diagnosis of the disease can be performed by fine needle aspiration biopsy guided by ultrasound and cytology or biopsy. The treatment of hepatic lipidosis is based on stabilizing the patient by supplying water and electrolyte losses and provide adequate nutritional support. The diet is usually provided through feeding tubes for a period ranging from 4 to 6 weeks may occur depending on the patient's condition. The prognosis for cats with hepatic lipidosis is favored in cases of identification followed by intensive treatment of underlying causes and for patients receiving therapy necessary in cases of idiopathic hepatic lipidosis.

  9. Inducible bilirubin oxidase: A novel function for the mouse cytochrome P450 2A5

    Abu-Bakar, A' edah, E-mail: a.abubakar@uq.edu.au [The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland (Australia); Arthur, Dionne Maioha [The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland (Australia); Cooperative Research Centre for Contamination Assessment and Remediation of the Environment, Adelaide (Australia); Aganovic, Simona [Department of Pharmaceutical Biosciences, Uppsala University, Biomedical Centre, Box 578, S-751 23 Uppsala (Sweden); Ng, Jack C. [The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland (Australia); Cooperative Research Centre for Contamination Assessment and Remediation of the Environment, Adelaide (Australia); Lang, Matti A. [The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland (Australia); Department of Pharmaceutical Biosciences, Uppsala University, Biomedical Centre, Box 578, S-751 23 Uppsala (Sweden)

    2011-11-15

    We have previously shown that bilirubin (BR), a breakdown product of haem, is a strong inhibitor and a high affinity substrate of the mouse cytochrome P450 2A5 (CYP2A5). The antioxidant BR, which is cytotoxic at high concentrations, is potentially useful in cellular protection against oxygen radicals if its intracellular levels can be strictly controlled. The mechanisms that regulate cellular BR levels are still obscure. In this paper we provide preliminary evidence for a novel function of CYP2A5 as hepatic 'BR oxidase'. A high-performance liquid chromatography/electrospray ionisation mass spectrometry screening showed that recombinant yeast microsomes expressing the CYP2A5 oxidise BR to biliverdin, as the main metabolite, and to three other smaller products with m/z values of 301, 315 and 333. The metabolic profile is significantly different from that of chemical oxidation of BR. In chemical oxidation the smaller products were the main metabolites. This suggests that the enzymatic reaction is selective, towards biliverdin production. Bilirubin treatment of primary hepatocytes increased the CYP2A5 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A5 compared to cells treated only with CHX. Collectively, the observations suggest that the CYP2A5 is potentially an inducible 'BR oxidase' where BR may accelerate its own metabolism through stabilization of the CYP2A5 protein. It is possible that this metabolic pathway is potentially part of the machinery controlling intracellular BR levels in transient oxidative stress situations, in which high amounts of BR are produced. -- Highlights: Black-Right-Pointing-Pointer CYP2A5 metabolizes bilirubin to biliverdin and dipyrroles. Black-Right-Pointing-Pointer Bilirubin increased the hepatic CYP2A5 protein and activity levels. Black-Right-Pointing-Pointer Bilirubin does not

  10. Inducible bilirubin oxidase: A novel function for the mouse cytochrome P450 2A5

    Abu-Bakar, A'edah; Arthur, Dionne Maioha; Aganovic, Simona; Ng, Jack C.; Lang, Matti A.

    2011-01-01

    We have previously shown that bilirubin (BR), a breakdown product of haem, is a strong inhibitor and a high affinity substrate of the mouse cytochrome P450 2A5 (CYP2A5). The antioxidant BR, which is cytotoxic at high concentrations, is potentially useful in cellular protection against oxygen radicals if its intracellular levels can be strictly controlled. The mechanisms that regulate cellular BR levels are still obscure. In this paper we provide preliminary evidence for a novel function of CYP2A5 as hepatic “BR oxidase”. A high-performance liquid chromatography/electrospray ionisation mass spectrometry screening showed that recombinant yeast microsomes expressing the CYP2A5 oxidise BR to biliverdin, as the main metabolite, and to three other smaller products with m/z values of 301, 315 and 333. The metabolic profile is significantly different from that of chemical oxidation of BR. In chemical oxidation the smaller products were the main metabolites. This suggests that the enzymatic reaction is selective, towards biliverdin production. Bilirubin treatment of primary hepatocytes increased the CYP2A5 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A5 compared to cells treated only with CHX. Collectively, the observations suggest that the CYP2A5 is potentially an inducible “BR oxidase” where BR may accelerate its own metabolism through stabilization of the CYP2A5 protein. It is possible that this metabolic pathway is potentially part of the machinery controlling intracellular BR levels in transient oxidative stress situations, in which high amounts of BR are produced. -- Highlights: ► CYP2A5 metabolizes bilirubin to biliverdin and dipyrroles. ► Bilirubin increased the hepatic CYP2A5 protein and activity levels. ► Bilirubin does not change the hepatic CYP2A5 mRNA levels. ► Co-treatment with a protein synthesis inhibitor

  11. Mechanistic Scrutiny Identifies a Kinetic Role for Cytochrome b5 Regulation of Human Cytochrome P450c17 (CYP17A1, P450 17A1.

    Alexandr N Simonov

    Full Text Available Cytochrome P450c17 (P450 17A1, CYP17A1 is a critical enzyme in the synthesis of androgens and is now a target enzyme for the treatment of prostate cancer. Cytochrome P450c17 can exhibit either one or two physiological enzymatic activities differentially regulated by cytochrome b5. How this is achieved remains unknown. Here, comprehensive in silico, in vivo and in vitro analyses were undertaken. Fluorescence Resonance Energy Transfer analysis showed close interactions within living cells between cytochrome P450c17 and cytochrome b5. In silico modeling identified the sites of interaction and confirmed that E48 and E49 residues in cytochrome b5 are essential for activity. Quartz crystal microbalance studies identified specific protein-protein interactions in a lipid membrane. Voltammetric analysis revealed that the wild type cytochrome b5, but not a mutated, E48G/E49G cyt b5, altered the kinetics of electron transfer between the electrode and the P450c17. We conclude that cytochrome b5 can influence the electronic conductivity of cytochrome P450c17 via allosteric, protein-protein interactions.

  12. Hepatitis C FAQs for the Public

    ... Hepatitis Contact Us Anonymous Feedback Quick Links to Hepatitis … A | B | C | D | E Viral Hepatitis Home ... Local Partners & Grantees Policy and Programs Resource Center Hepatitis C FAQs for the Public Recommend on Facebook ...

  13. Hepatitis B FAQs for the Public

    ... Professional Resources Patient Education Resources Quick Links to Hepatitis … A | B | C | D | E Viral Hepatitis Home ... Grantees Policy and Programs Resource Center Viral Hepatitis Hepatitis B Questions and Answers for the Public Recommend ...

  14. Alternative and Complementary Therapies for Hepatitis C

    ... and Complementary Therapies Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For Veterans and the Public Veterans ... treatments which have been proven to reduce the hepatitis C viral load. Just because something is "natural" (an herb, ...

  15. Viral Hepatitis: A through E and Beyond

    ... National Digestive Diseases Information Clearinghouse What is viral hepatitis? Viral hepatitis is inflammation of the liver caused by ... and serious. Drugs are available to treat chronic hepatitis. 4 Viral Hepatitis: A through E and Beyond What else ...

  16. Hepatic manifestations of celiac disease

    Hugh James Freeman

    2010-05-01

    Full Text Available Hugh James FreemanDepartment of Medicine (Gastroenterology, University of British Columbia, Vancouver, British Columbia, CanadaAbstract: Different hepatic and biliary tract disorders may occur with celiac disease. Some have been hypothesized to share genetic or immunopathogenetic factors, such as primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis. Other hepatic changes in celiac disease may occur with malnutrition resulting from impaired nutrient absorption, including hepatic steatosis. In addition, celiac disease may be associated with rare hepatic complications, such as hepatic T-cell lymphoma.Keywords: celiac disease, autoimmune liver disease, primary biliary cirrhosis, fatty liver, gluten-free diet

  17. Hepatic encephalopathy associated with hepatic lipidosis in llamas (Lama glama).

    Pillitteri, C A; Craig, L E

    2013-01-01

    Hepatic encephalopathy has been listed as a differential for llamas displaying neurologic signs, but it has not been histopathologically described. This report details the neurologic histopathologic findings associated with 3 cases of hepatic lipidosis with concurrent neurologic signs and compares them to 3 cases of hepatic lipidosis in the absence of neurologic signs and 3 cases without hepatic lipidosis. Brain from all 3 llamas displaying neurologic signs contained Alzheimer type II cells, which were not detected in either subset of llamas without neurologic signs. Astrocytic immunohistochemical staining intensity for glial fibrillary acid protein was decreased in llamas with neurologic signs as compared to 2 of 3 llamas with hepatic lipidosis and without neurologic signs and to 2 of 3 llamas without hepatic lipidosis. Immunohistochemical staining for S100 did not vary between groups. These findings suggest that hepatic encephalopathy may be associated with hepatic lipidosis in llamas.

  18. Severe atrophy of right hepatic lobe simulating right hepatic lobectomy

    Yeh, C.W.; Strashun, A.; Goldsmith, S.J.

    1981-01-01

    Absence of the right hepatic lobe following blunt abdominal trauma without surgical resection is reported. The usual site of the right hepatic lobe is demonstrated to be occupied by bowel by hepatobiliary imaging

  19. Suicide inactivation of cytochrome P-450 by methoxsalen. Evidence for the covalent binding of a reactive intermediate to the protein moiety

    Labbe, G.; Descatoire, V.; Beaune, P.; Letteron, P.; Larrey, D.; Pessayre, D.

    1989-01-01

    Incubation of rat liver microsomes with [3H]methoxsalen and NADPH resulted in the covalent binding of a methoxsalen intermediate to proteins comigrating with cytochromes P-450 UT-A, PB-B/D, ISF-G and PCN-E. Binding was increased by pretreatments with phenobarbital, beta-naphthoflavone (beta NF) and dexamethasone. Such pretreatments also increased the loss of CO-binding capacity either after administration of methoxsalen, or after incubation of hepatic microsomes with methoxsalen and NADPH. Immunoprecipitation of the methoxsalen metabolite-protein adducts in phenobarbital-induced microsomes was moderate with anti-UT-A antibodies, but marked with anti-PB-B/D and anti-PCN-E antibodies. Immunoprecipitation was observed also with anti-ISF-G (anti-beta NF-B) antibodies in beta NF-induced microsomes. Methoxsalen (0.25 mM) inhibited markedly the benzphetamine demethylase activity of phenobarbital-induced microsomes and the erythromycin demethylase activity of dexamethasone-induced microsomes. Whereas methoxsalen itself did not produce any binding spectrum, in contrast either in vivo administration of methoxsalen or incubation in vitro with methoxsalen and NADPH resulted in a low-to-high spin conversion of cytochrome P-450 as suggested by the appearance of a spectrum analogous to a type I binding spectrum. This low-to-high spin conversion was apparently due to a methoxsalen intermediate (probably, covalently bound to the protein and preventing partial sixth ligation of the iron). We conclude that suicide inactivation of cytochrome P-450 by methoxsalen is related to the covalent binding of a methoxsalen intermediate to the protein moiety of several cytochrome P-450 isoenzymes (including UT-A, PB-B/D, PCN-E as well as ISF-G and/or beta NF-B)

  20. Reduced cytochrome P4501A activity and recovery from oxidative stress during subchronic benzo[a]pyrene and benzo[e]pyrene treatment of rainbow trout

    Curtis, Lawrence R.; Garzon, Claudia B.; Arkoosh, Mary; Collier, Tracy; Myers, Mark S.; Buzitis, Jon; Hahn, Mark E.

    2011-01-01

    This study assessed the role of aryl hydrocarbon receptor (AHR) affinity, and cytochrome P4501A (CYP1A) protein and activity in polyaromatic hydrocarbon (PAH)-induced oxidative stress. In the 1-100 nM concentration range benzo[a]pyrene (BaP) but not benzo[e]pyrene (BeP) competitively displaced 2 nM [ 3 H]2, 3, 7, 8-tetrachloro-dibenzo-p-dioxin from rainbow trout AHR2α. Based on appearance of fluorescent aromatic compounds in bile over 3, 7, 14, 28 or 50 days of feeding 3 μg of BaP or BeP/g fish/day, rainbow trout liver readily excreted these polyaromatic hydrocarbons (PAHs) and their metabolites at near steady state rates. CYP1A proteins catalyzed more than 98% of ethoxyresorufin-O-deethylase (EROD) activity in rainbow trout hepatic microsomes. EROD activity of hepatic microsomes initially increased and then decreased to control activities after 50 days of feeding both PAHs. Immunohistochemistry of liver confirmed CYP1A protein increased in fish fed both PAHs after 3 days and remained elevated for up to 28 days. Neither BaP nor BeP increased hepatic DNA adduct concentrations at any time up to 50 days of feeding these PAHs. Comet assays of blood cells demonstrated marked DNA damage after 14 days of feeding both PAHs that was not significant after 50 days. There was a strong positive correlation between hepatic EROD activity and DNA damage in blood cells over time for both PAHs. Neither CYP1A protein nor 3-nitrotyrosine (a biomarker for oxidative stress) immunostaining in trunk kidney were significantly altered by BaP or BeP after 3, 7, 14, or 28 days. There was no clear association between AHR2α affinity and BaP and BeP-induced oxidative stress. - Highlights: → No direct association between aryl hydrocarbon receptor affinity and polyaromatic hydrocarbon induced oxidative stress. → There was a strong correlation between cytochrome P4501A activity and oxidative stress as measured with the comet assay. → There was no correlation between cytochrome P4501A

  1. Viral kinetics of the Hepatitis C virus

    F.C. Bekkering (Frank)

    2001-01-01

    textabstractHepatitis A virus and hepatitis B virus were identified as the cause of infectious hepatitis and serum hepatitis respectively in the beginning of the seventies. After introduction of screening tests for hepatitis A and B 4 only 25% of the cases of post transfusion hepatitis were found to

  2. Noninvasive diagnosis of hepatic fibrosis in chronic hepatitis C

    Stauber, Rudolf E; Lackner, Carolin

    2007-01-01

    Assessment of hepatic fibrosis is important for determining prognosis, guiding management decisions, and monitoring disease. Histological evaluation of liver biopsy specimens is currently considered the reference test for staging hepatic fibrosis. Since liver biopsy carries a small but significant risk, noninvasive tests to assess hepatic fibrosis are desirable. This editorial gives an overview on noninvasive methods currently available to determine hepatic fibrosis and their diagnostic accur...

  3. Seroprevalence and risk factors of Hepatitis B and Hepatitis C ...

    Undertaking blood transfusion, tattooing and sharing of needles were associated with hepatitis C infection (P=0.001). HBV was not associated with any of the risk factors (P>0.05). Conclusion: Our findings suggest a high prevalence of hepatitis B and hepatitis C among pregnant women; blood transfusion, tattooing and ...

  4. Attitudes and Awareness Regarding Hepatitis B and Hepatitis C ...

    in many cases hepatitis B and C can lead to permanent liver ... Department of Public Health Dentistry, Gian Sagar Dental College and Hospital, 1Department of Oral Surgery, Gian ... training among HCWs to prevent the spread of hepatitis B virus and hepatitis C virus. ..... primary care physicians following the Department of.

  5. Primary hepatic artery embolization in pediatric blunt hepatic trauma.

    Ong, Caroline C P; Toh, Luke; Lo, Richard H G; Yap, Te-Lu; Narasimhan, Kannan

    2012-12-01

    Non-operative management of isolated blunt hepatic trauma is recommended except when hemodynamic instability requires immediate laparotomy. Hepatic artery angioembolization is increasingly used for hepatic injuries with ongoing bleeding as demonstrated by contrast extravasation on the CT scan. It is used primarily or after laparotomy to control ongoing hemorrhage. Hepatic angioembolization as part of multimodality management of hepatic trauma is reported mainly in adults, with few pediatric case reports. We describe our institution experience with primary pediatric hepatic angioembolization and review the literature with regard to indications and complications. Two cases (3 and 8 years old), with high-grade blunt hepatic injuries with contrast extravasation on the CT scan were successfully managed by emergency primary hepatic angioembolization with minimal morbidity and avoided laparotomy. To date, the only reports of pediatric hepatic angioembolization for trauma are 5 cases for acute bleeding and 15 delayed cases for pseudoaneurysm. The role of hepatic angioembolization in the presence of an arterial blush on CT in adults is accepted, but contested in a pediatric series, despite higher transfusion rate and mortality rate. We propose that hepatic angioembolization should be considered adjunct treatment, in lieu of, or in addition to emergency laparotomy for hemostasis in pediatric blunt hepatic injury. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. Primary hepatic pheochromocytoma

    Rimmelin, A.; Hartheiser, M.; Gangi, A.; Welsch, M.; Jeung, M.Y.; Jaeck, D.; Tongio, J.; Dietemann, J.L.

    1996-01-01

    Pheochromocytomas are uncommon tumors that represent a potentially curable cause of hypertension. They are usually located in the adrenal glands, but 10% arise from extra-adrenal sites, located along the paravertebral sympathetic chains. We report a case of primary hepatic pheochromocytoma responsible for a severe hypertension in a 24-year-old man. Echotomography showed a lightly heterogeneous mass located in the segment 8 of the liver. Iodine 131 -metaiodobenzylguanidine scintigraphy showed a large hepatic concentration of the tracer and no other localization. This tumor appeared highly vascularized on enhanced CT scan and on aortic angiography. Magnetic resonance imaging revealed a hepatic tumor with a high signal intensity on T2-weighted images and with a signal isointense to the liver on T1-weighted images. The hepatic venous sampling contained the highest catecholamine level, whereas the adrenal venous samping was normal. After surgical resection of the hepatic tumor, the tension level and catecholamines plasmatic level normalized. No recurrent symptoms appeared during a 3-year follow-up. (orig.)

  7. Prevention of hepatitis B

    Marta Estera Kowalska

    2017-07-01

    Full Text Available Hepatitis B (Hepatitis B is a hepatitis B virus (HBV -based liver disease. This virus has an affinity for liver cells, it can cause both acute and chronic viral infections of varying severity. The consequences of chronic HBV infection can be cirrhosis and liver cancer. In Poland in 1989 a preventive program was implemented to reduce HBV infection. Universal vaccinations have been introduced to reduce the prevalence of Type B hepatitis B from 40.3 / 100,000 in 1989 to 7/100 in 2000. In the last 20 years in Poland there has been huge progress in the prevention and suppression of HBV infections. Decrease in the incidence of hepatitis B is mainly the result of the introduction of compulsory vaccination and improving hygiene procedures and improve sanitation aimed at aborting the pathways of the virus. However, still a large part of society is not immune on HBV infection acting potential group of the risk of infection. In addition, in the era of a growing group of followers. movements of the anti vaccine it is necessary to continue to promote knowledge of HBV and the efficacy and safety of vaccination.

  8. Hepatitis in pregnancy

    Ain, F.U.; Amin, A.; Yasmin, F.

    2007-01-01

    To determine the frequency of viral hepatitis in general, spectrum of hepatitis E in particular, and to study the maternal and fetal morbidity and mortality associated with it. In this prospective study, total number of pregnant women was 4723, sera of 35 pregnant women having clinical jaundice in pregnancy were analyzed for markers of hepatitis A , B, C and E viruses. Of the 35 pregnant women with jaundice HEV IgM were 60%,HA V IgM20%, Anti HCV 8.75%,Hbs Ag 5.71%, unexplained 5.71%. Amongst HEV 23.80% had hepatic encephalopathy DIC in 42.85%, PPH in 23.80%, renal failure in 9.52% an- maternal mortality in 4.76%. Approximately two third of pregnant women with HEV infection had preterm deliveries (76.19) % and perinatal mortality of 42.8%. Hepatitis E was the commonest etiological agent in those who had fulminant disease during pregnancy and was associated with high morbidity and mortality. (author)

  9. FastStats: Viral Hepatitis

    ... Submit What's this? Submit Button NCHS Home Viral Hepatitis Recommend on Facebook Tweet Share Compartir Data are for the U.S. Morbidity Number of new hepatitis A cases: 1,239 (2014) Number of new ...

  10. Bile acids for viral hepatitis

    Chen, Weikeng; Liu, J; Gluud, C

    2007-01-01

    Trials have assessed bile acids for patients with viral hepatitis, but no consensus has been reached regarding their usefulness.......Trials have assessed bile acids for patients with viral hepatitis, but no consensus has been reached regarding their usefulness....

  11. Hepatostomy for central hepatic hematomas

    Gewertz, B.L.; Olsen, W.R.

    1975-01-01

    Two patients with central hepatic hematomas are presented. Hepatostomy tube drainage provided prompt healing of the cavities without complications. The technique is presented as a safe and effective alternative to hepatic resection without compromising the established principles of management

  12. Nitazoxanide for chronic hepatitis C

    Nikolova, Kristiana; Gluud, Christian; Grevstad, Berit

    2014-01-01

    BACKGROUND: Hepatitis C infection is a disease of the liver caused by the hepatitis C virus. The estimated number of chronically infected people with hepatitis C virus worldwide is about 150 million people. Every year, another three to four million people acquire the infection. Chronic hepatitis C......) and ribavirin was the approved standard treatment for chronic hepatitis C. In 2011, first-generation direct-acting antivirals (DAAs) have been licensed, for use in combination with peginterferon and ribavirin for treating hepatitis C virus genotype 1 infection. Nitazoxanide is another antiviral drug with broad...... antiviral activity and may have potential as an effective alternative, or an addition to standard treatment for the treatment of the hepatitis C virus. OBJECTIVES: To assess the benefits and harms of nitazoxanide in people with chronic hepatitis C virus infection. SEARCH METHODS: We searched The Cochrane...

  13. Lansoprazole is an antituberculous prodrug targeting cytochrome bc1.

    Rybniker, Jan; Vocat, Anthony; Sala, Claudia; Busso, Philippe; Pojer, Florence; Benjak, Andrej; Cole, Stewart T

    2015-07-09

    Better antibiotics capable of killing multi-drug-resistant Mycobacterium tuberculosis are urgently needed. Despite extensive drug discovery efforts, only a few promising candidates are on the horizon and alternative screening protocols are required. Here, by testing a panel of FDA-approved drugs in a host cell-based assay, we show that the blockbuster drug lansoprazole (Prevacid), a gastric proton-pump inhibitor, has intracellular activity against M. tuberculosis. Ex vivo pharmacokinetics and target identification studies reveal that lansoprazole kills M. tuberculosis by targeting its cytochrome bc1 complex through intracellular sulfoxide reduction to lansoprazole sulfide. This novel class of cytochrome bc1 inhibitors is highly active against drug-resistant clinical isolates and spares the human H(+)K(+)-ATPase thus providing excellent opportunities for targeting the major pathogen M. tuberculosis. Our finding provides proof of concept for hit expansion by metabolic activation, a powerful tool for antibiotic screens.

  14. Variations in epidermal cytochrome oxidase activity after local irradiation

    Itoiz, M.E.; Rey, B.M. de; Cabrini, R.L.

    1982-01-01

    Cytochrome oxidase activity was evaluated histochemically as an index of mitochondrial damage after local irradiation with X-rays. It was determined by microphotometry on the tail skin of newly born Wistar rats four days after irradiation with doses ranging from 2 to 16krad. The enzyme activity of the whole epidermis increased after irradiation, the increases being related to the increase in thickness of the epithelium which was observed as a response to irradiation injury. Within the dose range tested, the enzyme concentration (expressed per unit volume of tissue) decreased in relation to the dose applied. At the electron microscopy level, the cytochemical demonstration of cytochrome oxidase revealed an irregular reaction over the cristae, intramitochondrial vacuolization and partial homogenization of the matrix. Positive membrane fragments were seen around lipid droplets. This reaction confirms the mitochondrial origin of these previously observed radiation-induced vacuoles. (author)

  15. Interaction of rocuronium with human liver cytochromes P450

    Anzenbacherova, Eva; Spicakova, Alena; Jourova, Lenka; Ulrichova, Jitka; Adamus, Milan; Bachleda, Petr; Anzenbacher, Pavel

    2015-01-01

    Rocuronium is a neuromuscular blocking agent acting as a competitive antagonist of acetylcholine. Results of an inhibition of eight individual liver microsomal cytochromes P450 (CYP) are presented. As the patients are routinely premedicated with diazepam, possible interaction of diazepam with rocuronium has been also studied. Results indicated that rocuronium interacts with human liver microsomal CYPs by binding to the substrate site. Next, concentration dependent inhibition of liver micro...

  16. Alcohol Use and Hepatitis C

    Peters, Marion G.; Terrault, Norah A.

    2002-01-01

    Excess alcohol consumption can worsen the course and outcome of chronic hepatitis C. It is important to distinguish between alcohol abuse, which must be treated on its own merits, and the effect of alcohol use on progression, severity, and treatment of hepatitis C. Most studies on the effects of alcohol on hepatitis C have focused on patients, with high levels of daily alcohol intake. Indeed, the adverse effects of light and moderate amounts of alcohol intake on hepatitis C virus (HCV) infect...

  17. Hepatitis in the United States

    2010-05-18

    In this podcast, Dr. John Ward, Director of CDC’s Division of Viral Hepatitis, discusses the different types of viral hepatitis and how they can be prevented. He also describes how hepatitis is transmitted and treated.  Created: 5/18/2010 by National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP).   Date Released: 5/18/2010.

  18. Coordinate regulation of cytochrome and alternative pathway respiration in tobacco.

    Vanlerberghe, G C; McIntosh, L

    1992-12-01

    In suspension cells of NT1 tobacco (Nicotiana tabacum L. cv bright yellow), inhibition of the cytochrome pathway of respiration with antimycin A induced a large increase in the capacity of the alternative pathway over a period of approximately 12 h, as confirmed in both whole cells and isolated mitochondria. The increase in alternative pathway capacity required de novo RNA and protein synthesis and correlated closely with the increase of a 35-kD alternative oxidase protein. When the cytochrome pathway of intact cells was inhibited by antimycin A, respiration proceeded exclusively through the alternative pathway, reached rates significantly higher than before antimycin A addition, and was not stimulated by p-trifluoromethoxycarbonylcyanide (FCCP). When inhibition of the cytochrome pathway was relieved, alternative pathway capacity and the level of the 35-kD alternative oxidase protein declined. Respiration rate also declined and could once again be stimulated by FCCP. These observations show that the capacities of the mitochondrial electron transport pathways can be regulated in a coordinate fashion.

  19. Monoclonal antibodies to drosophila cytochrome P-450's

    Sundseth, S.S.; Kennel, S.J.; Waters, L.C.

    1987-01-01

    Hybridomas producing monoclonal antibodies were prepared by the fusion of SP2/0 myeloma cells and spleen cells from a female BALB/c mouse immunized by cytochrome P-450-A and P-450-B purified from Drosophila Hikone-R (BG) microsomes. P-450-A and P-450-B are electrophoretically distinct subsets of Drosophila P-450. P-450-A is ubiquitous among strains tested, while P-450-B is present in only a few strains displaying unique enzyme activities and increased insecticide resistance. The Oregon-R strain contains only cytochromes P-450-A and is susceptible to insecticides. The authors Hikone-R (BG) strain expresses both cytochromes P-450-A and P-450-B and is insecticide resistant. Antibody producing hybridomas were detected in a solid-phase radioimmunoassay (RIA) by binding to Hikone-R (BG) or Oregon-R microsomes. Four independent hybridomas were identified as producing monoclonal antibodies that recognized proteins in the P-450 complex by immunoblot experiments. Three monoclonal antibodies recognized P-450-A proteins, while one monoclonal antibody bound predominantly P-450-B. This monoclonal antibody also recognized southern armyworm (Spodoptera eridania, Cramer) microsomal proteins

  20. Covalent modification of cytochrome c by reactive metabolites of furan.

    Phillips, Martin B; Sullivan, Mathilde M; Villalta, Peter W; Peterson, Lisa A

    2014-01-21

    Metabolism of the hepatotoxicant furan leads to protein adduct formation in the target organ. The initial bioactivation step involves cytochrome P450-catalyzed oxidation of furan, generating cis-2-butene-1,4-dial (BDA). BDA reacts with lysine to form pyrrolin-2-one adducts. Metabolic studies indicate that BDA also reacts with glutathione (GSH) to generate 2-(S-glutathionyl)butanedial (GSH-BDA), which then reacts with lysine to form GSH-BDA-lysine cross-links. To explore the relative reactivity of these two reactive intermediates, cytochrome c was reacted with BDA in the presence and absence of GSH. As judged by MALDI-TOF mass spectrometry, BDA reacts extensively with cytochrome c to form adducts that add 66 Da to the protein, consistent with the formation of pyrrolinone adducts. Addition of GSH to the reaction mixture reduced the overall extent of adduct formation. The mass of the adducted protein was shifted by 355 Da as expected for GSH-BDA-protein cross-link formation. LC-MS/MS analysis of the tryptic digests of the alkylated protein indicated that the majority of adducts occurred on lysine residues, with BDA reacting less selectively than GSH-BDA. Both types of adducts may contribute to the toxic effects of furan.

  1. Tributyltin interacts with mitochondria and induces cytochrome c release.

    Nishikimi, A; Kira, Y; Kasahara, E; Sato, E F; Kanno, T; Utsumi, K; Inoue, M

    2001-01-01

    Although triorganotins are potent inducers of apoptosis in various cell types, the critical targets of these compounds and the mechanisms by which they lead to cell death remain to be elucidated. There are two major pathways by which apoptotic cell death occurs: one is triggered by a cytokine mediator and the other is by a mitochondrion-dependent mechanism. To elucidate the mechanism of triorganotin-induced apoptosis, we studied the effect of tributyltin on mitochondrial function. We found that moderately low doses of tributyltin decrease mitochondrial membrane potential and induce cytochrome c release by a mechanism inhibited by cyclosporine A and bongkrekic acid. Tributyltin-induced cytochrome c release is also prevented by dithiols such as dithiothreitol and 2,3-dimercaptopropanol but not by monothiols such as GSH, N-acetyl-L-cysteine, L-cysteine and 2-mercaptoethanol. Further studies with phenylarsine oxide agarose revealed that tributyltin interacts with the adenine nucleotide translocator, a functional constituent of the mitochondrial permeability transition pore, which is selectively inhibited by dithiothreitol. These results suggest that, at low doses, tributyltin interacts selectively with critical thiol residues in the adenine nucleotide translocator and opens the permeability transition pore, thereby decreasing membrane potential and releasing cytochrome c from mitochondria, a series of events consistent with established mechanistic models of apoptosis. PMID:11368793

  2. Rational redesign of the biodegradative enzyme cytochrome P450 cam:

    Ornstein, R.; Paulsen, M.; Bass, M.; Arnold, G.

    1991-03-01

    Cytochromes P450, a superfamily of monooxygenase enzymes present in all kingdoms of living organisms, are very versatile with respect to substrate range and catalytic functionality. Many recalcitrant halogenated hydrocarbons, on DOE sites and throughout the nation, result in serious environmental impact. Cytochromes P450 have been shown to be catalytically capable of, at least partial, dehalogenation of some such compounds. Clearly, however, their active site stereochemistry and related functional components are not well suited for this role because the rates of dehalogenation are generally rather modest. The evolution of modified active site and access channel structures may proceed very slowly if multiple genetic changes are simultaneously required for enzyme adaptation. Since each mutational event is by itself a rare event, a basic premise of our research is that designing multiple changes into an enzyme may be more timely than waiting for them to occur biologically either via natural selection or under laboratory-controlled conditions. Starting with available high-resolution x-ray crystal structures, molecular modeling and molecular dynamics simulations have been used to probe the basic structure/function principles and conformational fluctuations of the biodegradative enzyme, cytochrome P450cam (camphor hydroxylase from Pseudomonas putida) and active site mutants, to provide the fundamental understanding necessary for rational engineering of the enzyme for modified substrate specificity. In the present paper, we review our progress to data, in the area of molecular dynamics simulations and active site redesign of P450cam. 36 refs., 2 figs

  3. Formation of putative chloroplast cytochromes in isolated developing pea chloroplasts

    Thaver, S.S.; Bhava, D.; Castelfranco, P.A.

    1986-01-01

    In addition to chlorophyll-protein complexes, other proteins were labeled when isolated developing pea chloroplasts were incubated with [ 14 C]-5-aminolevulinic acid [ 14 C]-ALA. The major labeled band (M/sub r/ = 43 kDa by LDS-PAGE) was labeled even in the presence of chloramphenicol. Heme-dependent peroxidase activity (as detected by the tetramethyl benzidine-H 2 O 2 stain) was not visibly associated with this band. The radioactive band was stable to heat, 5% HCl in acetone, and was absent if the incubation with [ 14 C]-5-aminolevulinic acid was carried out in the presence of N-methyl protoporphyrin IX dimethyl ester (a specific inhibitor of ferrochelatase). Organic solvent extraction procedures for the enrichment of cytochrome f from chloroplast membranes also extracted this unknown labeled product. It was concluded that this labeled product was probably a c-type cytochrome. The effect of exogenous iron, iron chelators, gabaculine (an inhibitor of ALA synthesis) and other incubation conditions upon the in vitro formation of putative chloroplast cytochromes will be discussed

  4. Role of cytochrome P450 genotype in the steps toward personalized drug therapy

    Cavallari LH

    2011-11-01

    Full Text Available Larisa H Cavallari1,2, Hyunyoung Jeong1,2, Adam Bress11Department of Pharmacy Practice, 2Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USAAbstract: Genetic polymorphism for cytochrome 450 (P450 enzymes leads to interindividual variability in the plasma concentrations of many drugs. In some cases, P450 genotype results in decreased enzyme activity and an increased risk for adverse drug effects. For example, individuals with the CYP2D6 loss-of-function genotype are at increased risk for ventricular arrhythmia if treated with usual does of thioridazine. In other cases, P450 genotype may influence the dose of a drug required to achieve a desired effect. This is the case with warfarin, with lower doses often necessary in carriers of a variant CYP2C9*2 or *3 allele to avoid supratherapeutic anticoagulation. When a prodrug, such as clopidogrel or codeine, must undergo hepatic biotransformation to its active form, a loss-of-function P450 genotype leads to reduced concentrations of the active drug and decreased drug efficacy. In contrast, patients with multiple CYP2D6 gene copies are at risk for opioid-related toxicity if treated with usual doses of codeine-containing analgesics. At least 25 drugs contain information in their US Food and Drug Administration-approved labeling regarding P450 genotype. The CYP2C9, CYP2C19, and CYP2D6 genes are the P450 genes most often cited. To date, integration of P450 genetic information into clinical decision making is limited. However, some institutions are beginning to embrace routine P450 genotyping to assist in the treatment of their patients. Genotyping for P450 variants may carry less risk for discrimination compared with genotyping for disease-associated variants. As such, P450 genotyping is likely to lead the way in the clinical implementation of pharmacogenomics. This review discusses variability in the CYP2C9, CYP2C19, and CYP2D6 genes and the

  5. Hepatic angiography: Portal hypertension

    Oliver, T.W. Jr.; Sones, P.J. Jr.

    1985-01-01

    Portal hypertension is usually a manifestation of underlying hepatic parenchymal disease, although it may be secondary to portal or hepatic venous thrombosis and rarely to hyperdynamic portal states. Portal hypertension may present as encephalopathy, ascites, jaundice, hepatic failure, or catastrophic upper gastrointestinal hemorrhage. Radiologic investigation should include indirect or direct measurements of portal pressure, assessment of portal venous perfusion, visualization of collaterals, and demonstration of arterial and venous anatomy for potential shunt procedure. Following survival of initial variceal bleeding, the most effective procedure to prevent recurrent hemorrhage is a shunt to decompress the varices. The decision whether to intervene medically or surgically during the acute hemorrhagic episode as well as the type of shunt used to prevent future hemorrhage is the subject of continuing controversy

  6. Prophylactic Hepatitis E Vaccine.

    Zhang, Jun; Zhao, Qinjian; Xia, Ningshao

    2016-01-01

    Hepatitis E has been increasingly recognized as an underestimated global disease burden in recent years. Subpopulations with more serious infection-associated damage or death include pregnant women, patients with basic liver diseases, and elderly persons. Vaccine would be the most effective means for prevention of HEV infection. The lack of an efficient cell culture system for HEV makes the development of classic inactive or attenuated vaccine infeasible. Hence, the recombinant vaccine approaches are explored deeply. The neutralizing sites are located almost exclusively in the capsid protein, pORF2, of the virion. Based on pORF2, many vaccine candidates showed potential of protecting primate animals; two of them were tested in human and evidenced to be well tolerated in adults and highly efficacious in preventing hepatitis E. The world's first hepatitis E vaccine, Hecolin ® (HEV 239 vaccine), was licensed in China and launched in 2012.

  7. [Hepatitis E as zoonosis].

    Baumann-Popczyk, Anna

    2011-01-01

    The hepatitis E virus (HEV) the causative agent of hepatitis E, is a non-enveloped RNA virus. HEV is transmitted through oral consumption of contaminated food and water According to the currently knowledge now be considered as zoonosis. The main reservoir of HEV are pigs, boars and deer. For the first time HEV was isolated from animals (pigs) in 1997 in the U.S. Genetic analysis of strains isolated from pigs showed high similarity to strains HEV isolated from humans. This was the first evidence showing that HEV is a zoonosis. Further studies have shown that occupational groups e.g. veterinarians, swine breeders with close contact to pigs have an increased risk for HEV infections. The additional evidence supported the zoonotic potential of HEV were reports of acute hepatitis E after the consumption of undercooked meat from deer and wild boar. Infection of HEV in the domestic pig and wild boar population in Europe is widespread.

  8. Hepatic artery aneurysms (HAAs)

    Nosratini, H.

    2004-01-01

    The hepatic artery aneurysms are rare, especially in interahepatic branches, The frequency consists of 75-80% extrahepatic and 20-25% intrahepatic. Catheterization is achieved usually from common femoral artery, other methods implemented in the case of unsuccessful catheterization from femoral artery, are translumbar and brachial catheterization. The study consist of 565 patients that were referred to the angiography ward, During seven years of assessment, five cases of hepatic artery aneurysm were found; this is a rare condition reported in the English literature. In the literature as well as in this case report the hepatic artery aneurysms are rare. In reported series the extrahepatic artery aneurysms are found more often than in the intrahepatic artery aneurysm but in this case report intrahepatic artery aneurysms are more than extrahepatic one. (author)

  9. Hepatitis Awareness Month PSA (:30)

    2011-05-11

    May is National Hepatitis Awareness Month. This 30 second PSA discusses hepatitis and encourages listners to talk to their health care professional about getting tested.  Created: 5/11/2011 by National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention.   Date Released: 5/11/2011.

  10. Canine Copper-Associated Hepatitis

    Dirksen, Karen; Fieten, Hille

    2017-01-01

    Copper-associated hepatitis is recognized with increasing frequency in dogs. The disease is characterized by centrolobular hepatic copper accumulation, leading to hepatitis and eventually cirrhosis. The only way to establish the diagnosis is by histologic assessment of copper distribution and copper

  11. Hepatitis A: Questions and Answers

    ... fluids enter another person’s bloodstream. • Hepatitis B and hepatitis C virus infections can cause chronic liver problems. Infection with hepa- ... there is no vaccine to protect people from hepatitis C virus infection. • There are medications that are approved by the ...

  12. Accessory hepatic vein: MR imaging

    Lee, Chang Hee; Rho, Tack Soo; Cha, Sang Hoon; Park, Cheol Min; Cha, In Ho

    1995-01-01

    To evaluate the MR appearance of the accessory hepatic veins. The study included 87 consecutive patients for whom abdominal MR images were obtained. The subjects who had liver lesion or hepatic vascular abnormalities were excluded. Couinaud classified accessory hepatic veins into inferior and middle right hepatic veins. Our major interests were evaluation of the incidence, morphology, and location of the accessory hepatic vein. Inferior right hepatic vein was demonstrated in 43 out of 87 patients (49%). The morphology was linear in 35 patients (80.5%), and V-shaped in 8 patients (19.5%). In 40 patients (93%), the inferior right hepatic vein was located in the posteroinferior aspect of the right lobe. Middle right hepatic vein was demonstrated in 7 out of 87 patients (8%). All were single linear in morphology, combined with the inferior right hepatic vein, and located between the right hepatic vein and inferior right hepatic vein. The accessory hepatic vein was demonstrated in 49% among the Korean adult population, and was located in posteroinferior portion of the liver, in 93%

  13. Conformational changes of the NADPH-dependent cytochrome P450 reductase in the course of electron transfer to cytochromes P450

    Laursen, Tomas; Jensen, Kenneth; Møller, Birger Lindberg

    2011-01-01

    The NADPH-dependent cytochrome P450 reductase (CPR) is a key electron donor to eucaryotic cytochromes P450 (CYPs). CPR shuttles electrons from NADPH through the FAD and FMN-coenzymes into the iron of the prosthetic heme-group of the CYP. In the course of these electron transfer reactions, CPR und...... to serve as an effective electron transferring "nano-machine"....

  14. In-silico assessment of protein-protein electron transfer. a case study: cytochrome c peroxidase--cytochrome c.

    Frank H Wallrapp

    Full Text Available The fast development of software and hardware is notably helping in closing the gap between macroscopic and microscopic data. Using a novel theoretical strategy combining molecular dynamics simulations, conformational clustering, ab-initio quantum mechanics and electronic coupling calculations, we show how computational methodologies are mature enough to provide accurate atomistic details into the mechanism of electron transfer (ET processes in complex protein systems, known to be a significant challenge. We performed a quantitative study of the ET between Cytochrome c Peroxidase and its redox partner Cytochrome c. Our results confirm the ET mechanism as hole transfer (HT through residues Ala194, Ala193, Gly192 and Trp191 of CcP. Furthermore, our findings indicate the fine evolution of the enzyme to approach an elevated turnover rate of 5.47 × 10(6 s(-1 for the ET between Cytc and CcP through establishment of a localized bridge state in Trp191.

  15. Structure and expression of cytochrome f in an Oenothera plastome mutant.

    Johnson, E M; Sears, B B

    1990-06-01

    The chloroplast mutant pm7 is one of a number of mutants derived from the plastome mutator (pm) line of Oenothera hookeri, strain Johansen. Immunoblotting showed that this mutant accumulates a protein that is cross-antigenic with cytochrome f, but five kilodaltons larger than the mature wild-type protein. Since cytochrome f is known to be translated on plastid ribosomes as a precursor with an amino-terminal extension, it is proposed that the unprocessed cytochrome f precursor accumulates in pm7. In addition to this precursor-sized cytochrome f protein, some mature-sized cytochrome f was also found in the mutant plastids. The pm7 mutation is inherited in a non-Mendelian fashion; but no alterations in chloroplast DNA restriction patterns, or differences in DNA sequence in the region encoding cytochrome f, were found in a comparison of the wild-type and pm7 chloroplast DNAs. Although the mutant was capable of synthesizing heme, no covalently-bound heme, normally found associated with mature, functional, cytochrome f was detected in the mutant at sizes expected for the presumed precursor, or for mature cytochrome f. These results indicate that the aberrant accumulation of a precursor-sized cytochrome f in pm7 is not due to a lesion directly in the plastid gene encoding cytochrome f, petA, or to a deficiency in the ability of the mutant plastids to synthesize or accumulate heme.

  16. Blood lipids analysis in patients with hepatitis and hepatic fibrosis

    Si Jianhong

    2007-01-01

    Objective: To investigate the correlationship between blood hepatic fibrosis markers and blood lipids levels. Methods: Serum hepatic fibrosis markers (HA, PC III, IV-C, LN) levels were determined with RIA and serum lipids (TG, TCh HDL; LDL, apoA1, apoB) were measured with biochemical methods in 98 patients with hepatitis in various stages and 50 controls. Liver biopsy was done in all the hepatitis patients. Results: Hepatic fibrosis was classified into 5 grades (S0-S4) according to the pathology shown in the biopsy specimen. The serum lipid levels decreased along with the increase of severity of fibrosis from S0 to S4. Levels in S4 patients were significantly lower than those in controls (P 0.05). Conclusion: The serum hepatic fibrosis markers levels increased and lipids levels decreased along with the progress of hepatitis from acute to cirrhosis. (authors)

  17. Plasmon waveguide resonance spectroscopic evidence for differential binding of oxidized and reduced rhodobacter capsulatus cytochrome c(2) to the cytochrome bc(1) complex mediated by the conformation of the rieske iron-sulfur protein

    Devanathan, S.; Salamon, Z.; Tollin, G.; Fitch, J.C.; Meyer, T.E.; Berry, E.A.; Cusanovich, M.A.

    2007-01-01

    The dissociation constants for the binding of Rhodobacter capsulatus cytochrome c2 and its K93P mutant to the cytochrome bc1 complex embedded in a phospholipid bilayer were measured by plasmon waveguide resonance spectroscopy in the presence and absence of the inhibitor stigmatellin. The reduced form of cytochrome c2 strongly binds to reduced cytochrome bc1 (Kd = 0.02 M) but binds much more weakly to the oxidized form (Kd = 3.1 M). In contrast, oxidized cytochrome c2 binds to oxidized cytochrome bc1 in a biphasic fashion with Kd values of 0.11 and 0.58 M. Such a biphasic interaction is consistent with binding to two separate sites or conformations of oxidized cytochrome c2 and/or cytochrome bc1. However, in the presence of stigmatellin, we find that oxidized cytochrome c2 binds to oxidized cytochrome bc1 in a monophasic fashion with high affinity (Kd = 0.06 M) and reduced cytochrome c2 binds less strongly (Kd = 0.11 M) but ∼30-fold more tightly than in the absence of stigmatellin. Structural studies with cytochrome bc1, with and without the inhibitor stigmatellin, have led to the proposal that the Rieske protein is mobile, moving between the cytochrome b and cytochrome c1 components during turnover. In one conformation, the Rieske protein binds near the heme of cytochrome c1, while the cytochrome c2 binding site is also near the cytochrome c1 heme but on the opposite side from the Rieske site, where cytochrome c2 cannot directly interact with Rieske. However, the inhibitor, stigmatellin, freezes the Rieske protein iron-sulfur cluster in a conformation proximal to cytochrome b and distal to cytochrome c1. We conclude from this that the dual conformation of the Rieske protein is primarily responsible for biphasic binding of oxidized cytochrome c2 to cytochrome c1. This optimizes turnover by maximizing binding of the substrate, oxidized cytochrome c2, when the iron-sulfur cluster is proximal to cytochrome b and minimizing binding of the product, reduced cytochrome c

  18. In vitro effects of myricetin, morin, apigenin, (+)-taxifolin, (+)-catechin, (−)-epicatechin, naringenin and naringin on cytochrome b5 reduction by purified NADH-cytochrome b5 reductase

    Çelik, Haydar; Koşar, Müberra; Arinç, Emel

    2013-01-01

    Highlights: • We assessed inhibitory effects of 8 dietary flavonoids on cytochrome b5 reduction by purified NADH-cytochrome b5 reductase. • The flavonol myricetin was the most potent in inhibiting cytochrome b5 reduction with an IC 50 value of 0.35 μM. • We investigated kinetics of myricetin-induced inhibition in detail. • We explored the structure–inhibitory activity relationship of compounds. • Modulation of cytochrome b5 reduction indicates a potential for myricetin to lead to some food–drug/xenobiotic interactions. - Abstract: The microsomal NADH-dependent electron transport system consisting of cytochrome b5 reductase and cytochrome b5 participates in a number of physiologically important processes including lipid metabolism as well as is involved in the metabolism of various drug and xenobiotics. In the present study, we assessed the inhibitory effects of eight dietary flavonoids representing five distinct chemical classes on cytochrome b5 reduction by purified cytochrome b5 reductase. From the flavonoids tested, myricetin was the most potent in inhibiting cytochrome b5 reduction with an IC 50 value of 0.35 μM. Myricetin inhibited b5 reductase noncompetitively with a K i of 0.21 μM with respect to cofactor NADH, and exhibited a non-linear relationship indicating non-Michaelis–Menten kinetic binding with respect to cytochrome b5. In contrast to the potent inhibitory activity of myricetin, (+)-taxifolin was found to be a weak inhibitor (IC 50 = 9.8 μM). The remaining flavonoids were inactive within the concentration range tested (1–50 μM). Analysis of structure–activity data suggested that simultaneous presence of three OH groups in ring B is a primary structural determinant for a potent enzyme inhibition. Our results suggest that inhibition of the activity of this system by myricetin or myricetin containing diets may influence the metabolism of therapeutic drugs as well as detoxification of xenobiotics

  19. Hepatitis C in India

    PRAKASH KUMAR

    positivity rates in these patients, accounting for nearly 24-. 28% of cases. .... Author. Punjab. Blood donors. 44,064. ELISA. 1.09%. Gupta et al 2004. Delhi. Voluntary blood ... contribution of hepatitis C in these disease conditions is summarized ...

  20. XTC-induced hepatitis

    Oranje, W.A.; van Pol, V.; van der Wurff, A.A.; Zeijen, R.N.; Stockbrügger, R.W.; Arends, J.W.

    1994-01-01

    XTC-induced hepatitis. Oranje WA, von Pol P, vd Wurff A, Zeijen RN, Stockbrugger RW, Arends JW. Department of Internal Medicine, University Hospital, Maastricht, Netherlands. An increasing number of severe complications associated with the use of XTC is being reported. After 11 earlier case reports

  1. Management of Hepatic Encephalopathy

    G. Wright

    2011-01-01

    Full Text Available Hepatic encephalopathy (HE, the neuropsychiatric presentation of liver disease, is associated with high morbidity and mortality. Reduction of plasma ammonia remains the central therapeutic strategy, but there is a need for newer novel therapies. We discuss current evidence supporting the use of interventions for both the general management of chronic HE and that necessary for more acute and advanced disease.

  2. Hepatic steatosis : metabolic consequences

    Boer, Adriana Maria den

    2006-01-01

    In this thesis we focused on the causes and consequences of hepatic steatosis. Epidemiological studies in humans, as well as experimental studies in animal models, have shown an association between visceral obesity and dyslipidemia, insulin resistance and type 2 diabetes mellitus. The mechanism

  3. Immigration and viral hepatitis

    S. Sharma (Suraj); M. Carballo (Manuel); J.J. Feld (Jordan J.); H.L.A. Janssen (Harry)

    2015-01-01

    textabstractWHO estimates reveal that the global prevalence of viral hepatitis may be as high as 500 million, with an annual mortality rate of up to 1.3 million individuals. The majority of this global burden of disease is borne by nations of the developing world with high rates of vertical and

  4. IMPROVING STRUCTURE-LINKED ACCESS TO PUBLICLY AVAILABLE CHEMICAL TOXICITY INFORMATION

    Hepatotoxicity of the Herbicide Alachlor Associated with Glutathione Depletion, Oxidative Damage and Protein S-Cysteinyl Adduction.Toxicity of the herbicide alachlor (2-chloro-2',6'-diethtl-N-[methoxtmethtl]-acetanilide) has been attributed to cytochrome P450-dependent me...

  5. Exposure to a northern contaminant mixture (NCM alters hepatic energy and lipid metabolism exacerbating hepatic steatosis in obese JCR rats.

    Ryan J Mailloux

    Full Text Available Non-alcoholic fatty liver disease (NAFLD, defined by the American Liver Society as the buildup of extra fat in liver cells that is not caused by alcohol, is the most common liver disease in North America. Obesity and type 2 diabetes are viewed as the major causes of NAFLD. Environmental contaminants have also been implicated in the development of NAFLD. Northern populations are exposed to a myriad of persistent organic pollutants including polychlorinated biphenyls, organochlorine pesticides, flame retardants, and toxic metals, while also affected by higher rates of obesity and alcohol abuse compared to the rest of Canada. In this study, we examined the impact of a mixture of 22 contaminants detected in Inuit blood on the development and progression of NAFLD in obese JCR rats with or without co-exposure to 10% ethanol. Hepatosteatosis was found in obese rat liver, which was worsened by exposure to 10% ethanol. NCM treatment increased the number of macrovesicular lipid droplets, total lipid contents, portion of mono- and polyunsaturated fatty acids in the liver. This was complemented by an increase in hepatic total cholesterol and cholesterol ester levels which was associated with changes in the expression of genes and proteins involved in lipid metabolism and transport. In addition, NCM treatment increased cytochrome P450 2E1 protein expression and decreased ubiquinone pool, and mitochondrial ATP synthase subunit ATP5A and Complex IV activity. Despite the changes in mitochondrial physiology, hepatic ATP levels were maintained high in NCM-treated versus control rats. This was due to a decrease in ATP utilization and an increase in creatine kinase activity. Collectively, our results suggest that NCM treatment decreases hepatic cholesterol export, possibly also increases cholesterol uptake from circulation, and promotes lipid accumulation and alters ATP homeostasis which exacerbates the existing hepatic steatosis in genetically obese JCR rats with

  6. Metabolism of bilirubin by human cytochrome P450 2A6

    Abu-Bakar, A' edah, E-mail: a.abubakar@uq.edu.au [The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland (Australia); Arthur, Dionne M. [The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland (Australia); Cooperative Research Centre for Contamination Assessment and Remediation of the Environment, Adelaide (Australia); Wikman, Anna S. [The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland (Australia); Department of Pharmaceutical Biosciences, Uppsala University, SE-75123 Uppsala (Sweden); Rahnasto, Minna; Juvonen, Risto O.; Vepsäläinen, Jouko; Raunio, Hannu [School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, POB 1627, 70211 Kuopio (Finland); Ng, Jack C. [The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland (Australia); Cooperative Research Centre for Contamination Assessment and Remediation of the Environment, Adelaide (Australia); Lang, Matti A. [The University of Queensland, National Research Centre for Environmental Toxicology (Entox), 4072 Brisbane, Queensland (Australia)

    2012-05-15

    The mouse cytochrome P450 (CYP) 2A5 has recently been shown to function as hepatic “Bilirubin Oxidase” (Abu-Bakar, A., et al., 2011. Toxicol. Appl. Pharmacol. 257, 14–22). To date, no information is available on human CYP isoforms involvement in bilirubin metabolism. In this paper we provide novel evidence for human CYP2A6 metabolising the tetrapyrrole bilirubin. Incubation of bilirubin with recombinant yeast microsomes expressing the CYP2A6 showed that bilirubin inhibited CYP2A6-dependent coumarin 7-hydroxylase activity to almost 100% with an estimated K{sub i} of 2.23 μM. Metabolite screening by a high-performance liquid chromatography/electrospray ionisation mass spectrometry indicated that CYP2A6 oxidised bilirubin to biliverdin and to three other smaller products with m/z values of 301, 315 and 333. Molecular docking analyses indicated that bilirubin and its positively charged intermediate interacted with key amino acid residues at the enzyme's active site. They were stabilised at the site in a conformation favouring biliverdin formation. By contrast, the end product, biliverdin was less fitting to the active site with the critical central methylene bridge distanced from the CYP2A6 haem iron facilitating its release. Furthermore, bilirubin treatment of HepG2 cells increased the CYP2A6 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A6 compared to cells treated only with CHX. Collectively, the observations indicate that the CYP2A6 may function as human “Bilirubin Oxidase” where bilirubin is potentially a substrate and a regulator of the enzyme. -- Highlights: ► Human CYP2A6 interacts with bilirubin with a high affinity. ► Bilirubin docking to the CYP2A6 active site is more stable than biliverdin docking. ► Recombinant CYP2A6 microsomes metabolised bilirubin to biliverdin. ► Bilirubin increased the hepatic

  7. Metabolism of bilirubin by human cytochrome P450 2A6

    Abu-Bakar, A'edah; Arthur, Dionne M.; Wikman, Anna S.; Rahnasto, Minna; Juvonen, Risto O.; Vepsäläinen, Jouko; Raunio, Hannu; Ng, Jack C.; Lang, Matti A.

    2012-01-01

    The mouse cytochrome P450 (CYP) 2A5 has recently been shown to function as hepatic “Bilirubin Oxidase” (Abu-Bakar, A., et al., 2011. Toxicol. Appl. Pharmacol. 257, 14–22). To date, no information is available on human CYP isoforms involvement in bilirubin metabolism. In this paper we provide novel evidence for human CYP2A6 metabolising the tetrapyrrole bilirubin. Incubation of bilirubin with recombinant yeast microsomes expressing the CYP2A6 showed that bilirubin inhibited CYP2A6-dependent coumarin 7-hydroxylase activity to almost 100% with an estimated K i of 2.23 μM. Metabolite screening by a high-performance liquid chromatography/electrospray ionisation mass spectrometry indicated that CYP2A6 oxidised bilirubin to biliverdin and to three other smaller products with m/z values of 301, 315 and 333. Molecular docking analyses indicated that bilirubin and its positively charged intermediate interacted with key amino acid residues at the enzyme's active site. They were stabilised at the site in a conformation favouring biliverdin formation. By contrast, the end product, biliverdin was less fitting to the active site with the critical central methylene bridge distanced from the CYP2A6 haem iron facilitating its release. Furthermore, bilirubin treatment of HepG2 cells increased the CYP2A6 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A6 compared to cells treated only with CHX. Collectively, the observations indicate that the CYP2A6 may function as human “Bilirubin Oxidase” where bilirubin is potentially a substrate and a regulator of the enzyme. -- Highlights: ► Human CYP2A6 interacts with bilirubin with a high affinity. ► Bilirubin docking to the CYP2A6 active site is more stable than biliverdin docking. ► Recombinant CYP2A6 microsomes metabolised bilirubin to biliverdin. ► Bilirubin increased the hepatic CYP2A6

  8. R-warfarin clearances from plasma associated with polymorphic cytochrome P450 2C19 and simulated by individual physiologically based pharmacokinetic models for 11 cynomolgus monkeys.

    Utoh, Masahiro; Kusama, Takashi; Miura, Tomonori; Mitsui, Marina; Kawano, Mirai; Hirano, Takahiro; Shimizu, Makiko; Uno, Yasuhiro; Yamazaki, Hiroshi

    2018-02-01

    1. Cynomolgus monkey cytochrome P450 2C19 (formerly known as P450 2C75), homologous to human P450 2C19, has been identified as R-warfarin 7-hydroxylase. In this study, simulations of R-warfarin clearance in individual cynomolgus monkeys genotyped for P450 2C19 p.[(Phe100Asn; Ala103Val; Ile112Leu)] were performed using individual simplified physiologically based pharmacokinetic (PBPK) modeling. 2. Pharmacokinetic parameters and absorption rate constants, volumes of the systemic circulation, and hepatic intrinsic clearances for individual PBPK models were estimated for eleven cynomolgus monkeys. 3. One-way ANOVA revealed significant effects of the genotype (p warfarin among the homozygous mutant, heterozygous mutant, and wild-type groups. R-Warfarin clearances in individual cynomolgus monkeys genotyped for P450 2C19 were simulated by simplified PBPK modeling. The modeled hepatic intrinsic clearances were significantly associated with the P450 2C19 genotypes. The liver microsomal elimination rates of R-warfarin for individual animals after in vivo administration showed significant reductions associated with the genotype (p warfarin and related medicines associated with polymorphic P450 2C19 in individual cynomolgus monkeys, thereby facilitating calculation of the fraction of hepatic clearance.

  9. Crystalline silica is a negative modifier of pulmonary cytochrome P-4501A1 induction

    Battelli, L.A.; Ghanem, M.M.; Kashon, M.L.; Barger, M.; Ma, J.Y.C.; Simoskevitz, R.L.; Miles, P.R.; Hubbs, A.F. [NIOSH, Morgantown, WV (United States). Health Effects Laboratory Division

    2008-07-01

    Polycyclic aromatic hydrocarbons (PAHs) are products of incomplete combustion that are commonly inhaled by workers in the dusty trades. Many PAHs are metabolized by cytochrome P-4501A1 (CYP1A1), which may facilitate excretion but may activate pulmonary carcinogens. PAHs also stimulate their own metabolism by inducing CYP1A1. Recent studies suggest that respirable coal dust exposure inhibits induction of pulmonary CYP1A1 using the model PAH {beta}-naphthoflavone. The effect of the occupational particulate respirable crystalline silica was investigated on PAH-dependent pulmonary CYP1A1 induction. Male Sprague-Dawley rats were exposed to intratracheal silica or vehicle and then intraperitoneal {beta}-naphthoflavone, a CYP1A1 inducer, and/or phenobarbital, an inducer of hepatic CYP2B1, or vehicle. {beta}-Naphthoflavone induced pulmonary CYP1A1, but silica attenuated this {beta}-naphthoflavone-induced CYP1A1 activity and also suppressed the activity of CYP2B1, the major constituitive CYP in rat lung. The magnitude of CYP activity suppression was similar regardless of silica exposure dose within a range of 5 to 20 mg/rat. Phenobarbital and beta-naphthoflavone had no effect on pulmonary CYP2B1 activity. Both enzymatic immunohistochemistry and immunofluorescent staining for CYP1A1 indicated that sites of CYP1A1 induction were nonciliated airway epithelial cells, endothelial cells, and the alveolar septum. Our findings suggest that in PAH-exposed rat lung, silica is a negative modifier of CYP1A1 induction and CYP2B1 activity.

  10. The amino acid sequence of cytochrome c from Cucurbita maxima L. (pumpkin)

    Thompson, E. W.; Richardson, M.; Boulter, D.

    1971-01-01

    The amino acid sequence of pumpkin cytochrome c was determined on 2μmol of protein. Some evidence was found for the occurrence of two forms of cytochrome c, whose sequences differed in three positions. Pumpkin cytochrome c consists of 111 residues and is homologous with mitochondrial cytochromes c from other plants. Experimental details are given in a supplementary paper that has been deposited as Supplementary Publication SUP 50005 at the National Lending Library for Science and Technology, Boston Spa, Yorks. LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1971), 121, 7. PMID:5131733

  11. 77 FR 45895 - World Hepatitis Day, 2012

    2012-08-02

    ... Proclamation Worldwide, one in twelve people is living with viral hepatitis--a disease that threatens the... ourselves to the fight against viral hepatitis. Hepatitis prevention and control begins with awareness. Though all types of viral hepatitis are associated with serious health issues, hepatitis B and C can...

  12. Covalent Modification of Cytochrome C by Reactive Metabolites of Furan

    Phillips, Martin B.; Sullivan, Mathilde M.; Villalta, Peter W.; Peterson, Lisa A.

    2013-01-01

    Metabolism of the hepatotoxicant furan leads to protein adduct formation in the target organ. The initial bioactivation step involves cytochrome P450-catalyzed oxidation of furan, generating cis-2-butene-1,4-dial (BDA). BDA reacts with lysine to form pyrrolin-2-one adducts. Metabolic studies indicate that BDA also reacts with glutathione (GSH) to generate 2-(S-glutathionyl)butanedial (GSH-BDA), which then reacts with lysine to form GSH-BDA-lysine cross-links. To explore the relative reactivit...

  13. Redox Thermodynamics of Cytochromes c Subjected to Urea Induced Unfolding

    Monari, S.; Ranieri, A.; Di Rocco, G.; van der Zwan, G.; Peressini, S.; Tavagnacco, C.; Millo, D.; Borsari, M.

    2009-01-01

    The thermodynamics of the electron transfer (ET) process for beef heart and yeast cytochromes c and the Lys72Ala/Lys73Ala/Lys79Ala mutant of the latter species subjected to progressive urea-induced unfolding was determined electrochemically. The results indicate the presence of at least three protein forms which were assigned to a low-temperature and a high-temperature His-Met intermediate species and a bis-histidinate form (although the presence of a His-Lys form cannot be excluded). The muc...

  14. Enzymes activities involving bacterial cytochromes incorporated in clays

    Lojou, E.; Giudici-Orticoni, M.Th.; Bianco, P.

    2005-01-01

    With the development of bio electrochemistry, researches appeared on the enzymes immobilization at the surface of electrodes for the realization of bioreactors and bio sensors. One of the main challenges is the development of host matrix able to immobilize the protein material preserving its integrity. In this framework the authors developed graphite electrodes modified by clay films. These electrodes are examined for two enzyme reactions involving proteins of sulfate-reduction bacteria. Then in the framework of the hydrogen biological production and bioreactors for the environmental pollution de-pollution, the electrochemical behavior of the cytochrome c3 in two different clays deposed at the electrode is examined

  15. Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers

    Lee, C; Gong, Yanzhang; Brok, J

    2006-01-01

    Hepatitis B vaccine and hepatitis B immunoglobulin are considered for newborn infants of HBsAg-positive mothers to prevent hepatitis B infection.......Hepatitis B vaccine and hepatitis B immunoglobulin are considered for newborn infants of HBsAg-positive mothers to prevent hepatitis B infection....

  16. Changing Epidemiology of Hepatitis A and Hepatitis E Viruses in China, 1990-2014.

    Ren, Xiang; Wu, Peng; Wang, Liping; Geng, Mengjie; Zeng, Lingjia; Zhang, Jun; Xia, Ningshao; Lai, Shengjie; Dalton, Harry R; Cowling, Benjamin J; Yu, Hongjie

    2017-02-01

    We compared the epidemiology of hepatitis A and hepatitis E cases in China from 1990-2014 to better inform policy and prevention efforts. The incidence of hepatitis A cases declined dramatically, while hepatitis E incidence increased. During 2004-2014, hepatitis E mortality rates surpassed those of hepatitis A.

  17. Reduction of reversed micelle entrapped cytochrome c and cytochrome c3 by electrons generated by pulse radiolysis or by pyrene photoionization

    Vlsser, A.J.W.G.; Fendler, J.H.

    1982-01-01

    Horse heart cytochrome c and cytochrome c 3 , isolated from Desulfovibrio vulgaris, have been incorporated in sodium bis(2-ethylhexyl)sulfosuccinate (AOT) entrapped water pools in heptane. The absorption spectra of the cytochromes have been found to be strongly dependent on the water to AOT concentration ratios. The proteins solubilized in heptane by the AOT reversed micelles have retained their ability to mediate electron transfer. They reacted very rapidly with hydrated electrons, generated pulse radiolytically or, alternatively, formed in the laser photoionization of pyrene

  18. Voriconazole-Induced Hepatitis via Simvastatin- and Lansoprazole-Mediated Drug Interactions: A Case Report and Review of the Literature.

    Lopez, Jose Luis; Tayek, John A

    2016-01-01

    Therapeutic voriconazole concentrations have a narrow window of effectiveness before causing cholestatic hepatitis. After undergoing 1 year of voriconazole therapy for pulmonary aspergillosis, a 44-year-old man began treatment with 30 mg lansoprazole for gastroesophageal reflux symptoms. Within 5 days of starting treatment with lansoprazole, the patient presented with fatigue, jaundice, and cholestatic hepatitis. The hepatitis promptly resolved after stopping lansoprazole treatment. Sixteen months later, the patient was given simvastatin therapy, as recommended by the American Diabetes Association to prevent cardiovascular disease for patients with diabetes who are aged >40 years and have one additional risk factor. Within 2 weeks of taking simvastatin, a 3-hydroxy-3-methylglutaryl CoA reductase (statin) therapy, the patient redeveloped fatigue, jaundice, and cholestatic hepatitis. He described both episodes of fatigue and jaundice similarly in terms of onset and intensity. Voriconazole is metabolized by both CYP2C19 and CYP3A4 isoenzymes. Lansoprazole is an inhibitor of the CYP2C19 isoenzyme. Competition between voriconazole and lansoprazole likely led to increased voriconazole serum concentration and acute cholestatic hepatitis in this patient. Simvastatin inhibits the CYP3A4 isoenzyme. After the patient took 10 mg simvastatin daily for 2 weeks, cholestatic hepatitis occurred. The voriconazole concentration remained elevated (4.1 μg/ml) when measured 15 days after stopping simvastatin. The patient's Naranjo Adverse Drug Reaction Probability Scale score of 7 revealed that the cholestatic hepatitis was probably precipitated by lansoprazole. Likewise, the patient's Naranjo score of 9 also revealed that cholestatic hepatitis was attributable to a definite adverse drug reaction precipitated by the addition of simvastatin to the stable baseline regimen of voriconazole. In a single patient, two different inhibitors of the cytochrome P450 pathway stimulated voriconazole

  19. Occult hepatitis B among Iranian hepatitis C patients

    Ahmad shavakhi

    2009-02-01

    Full Text Available

    • BACKGROUND: Occult hepatitis B is defined as presence of HBV DNA in tissue or serum without hepatitis B surface antigen. The aim of this study is to determine frequency of occult hepatitis B among hepatitis C patients in Tehran and compare the route of transmission and liver enzymes between positive and negative HBV DNA patients.
    • METHODS: In a cross sectional study, serum of 103 hepatitis C cases (79.6% men and 20.4% women were analyzed for s, x and core genes via a nested polymerase chain reaction technique.
    • RESULTS: HBV DNA was detectable in serum of 20 patients (19.4%. No significant difference in age, sex and route of transmission were seen in HBV DNA positive and negative patients. In HBV DNA positive and negative groups, mean of AST was 73, 47 (p < 0.05 and mean of ALT was 76 and 36 respectively (p < 0.05.
    • CONCLUSION: Occult hepatitis B was observed in a considerable number of hepatitis C patients in Tehran. It was associated with elevation in liver enzyme but was not related to route of transmission.
    • KEY WORD: Occult hepatitis B, hepatitis C, cirrhosis.

  20. Fulminant Hepatic Failure Secondary to Primary Hepatic Angiosarcoma

    Ayokunle T. Abegunde

    2015-01-01

    Full Text Available Background. Hepatic angiosarcoma is a rare and aggressive tumor that often presents at an advanced stage with nonspecific symptoms. Objective. To report a case of primary hepatic angiosarcoma in an otherwise healthy man with normal liver function tests two months prior to presenting with a short period of jaundice that progressed to fulminant hepatic failure. Methods. Case report and review of literature. Conclusion. This case illustrates the rapidity of progression to death after the onset of symptoms in a patient with hepatic angiosarcoma. Research on early diagnostic strategies and newer therapies are needed to improve prognosis in this rare and poorly understood malignancy with limited treatment options.

  1. Ethylbenzene induces microsomal oxygen free radical generation: antibody-directed characterization of the responsible cytochrome P450 enzymes.

    Serron, S C; Dwivedi, N; Backes, W L

    2000-05-01

    Small aromatic hydrocarbons cause changes in oxidative metabolism by modulating the levels of cytochrome P450 enzymes, with the changes in these enzymes being responsible for qualitative changes in aromatic hydrocarbon metabolism. The goal of this study was to determine if exposure to the small alkylbenzene ethylbenzene (EB) leads to an increase in hepatic free radical production. Male F344 rats were treated with ip injections of EB (10 mmol/kg) and compared to corn oil controls. Hepatic free radical production was examined by measuring the conversion of 2',7'-dichlorofluorescin diacetate (DCFH-DA) to its fluorescent product 2',7'-dichlorofluorescein (DCF). A significant elevation of fluorescent DCF production was observed after treatment with EB, despite the lack of effect on overall cytochrome P450 levels. This process was shown to be inhibitable by metyrapone, an inhibitor of P450. DCF production was also inhibited by catalase, suggesting that hydrogen peroxide (H(2)O(2)) is one of the reactive oxygen intermediates involved in EB-mediated reactive oxygen species (ROS) formation. Interestingly, superoxide dismutase (SOD) did not inhibit DCF production in corn oil-treated rats but was an effective inhibitor in the EB-treated groups. In an effort to determine if the increase in ROS production was related to changes in specific P450 enzymes, DCF production was measured in the presence of anti-CYP2B, anti-CYP2C11, anti-CYP2E1, and anti-CYP3A2 inhibitory antibodies. Anti-CYP2B antibodies inhibited DCF production in EB-treated, but not corn oil groups, which is consistent with the low constitutive levels of this enzyme and its induction by EB. The data also demonstrate that CYP2B contributes to ROS production. Anti-CYP2C11 did not influence DCF production in either group. ROS formation in corn oil-treated rats as well as in ethylbenzene-treated rats was also inhibited with antibodies to anti-CYP2E1 and anti-CYP3A2. These results suggest that CYP2C11 does not appear to

  2. Hepatitis viral aguda

    Héctor Rubén Hernández Garcés

    1998-10-01

    Full Text Available Se realizó una revisión bibliográfica de las hepatitis virales agudas sobre aspectos vinculados a su etiología. Se tuvieron en cuenta además algunos datos epidemiológicos, las formas clínicas más importantes, los exámenes complementarios con especial énfasis en los marcadores virales y el diagnóstico positivoA bibliographical review of acute viral hepatitis was made taking into account those aspects connected with its etiology. Some epidemiological markers, the most important clinical forms, and the complementary examinations with special emphasis on the viral markers and the positive diagnosis were also considered

  3. Congenital Hepatic Cyst

    Aldo Recinos

    2017-04-01

    Full Text Available Congenital hepatic cyst is a rare and nonsymptomatic condition in infants and children. Its incidence is 2.5% in the postnatal life with a much lower incidence in the prenatal period. Incidental finding on antenatal imaging is the most common presentation. We present a case of a newborn in whom fetal ultrasound detected a cyst within the fetal liver. Postnatal imaging revealed a liver cyst in the right lobe of the liver, with no other intrahepatic structure affected. Liver function tests were abnormal, but the patient was asymptomatic. Posterior follow-up imaging showed a minor decrease in size. Management of congenital hepatic cyst is usually conservative, done with periodic ultrasound monitoring. However, surgical treatment is the mainstay of treatment when hydrops, progressive enlargement, hemorrhage, torsion, or compression of adjacent structures occurs. Malignant transformation can occur, but it is extremely rare. Partial or total removal of the cyst is the preferred treatment in neonates with a large lesion.

  4. Hepatic lipidosis in turkeys.

    Gazdzinski, P; Squires, E J; Julian, R J

    1994-01-01

    Two flocks of 14,000 twenty-week-old turkey hens each experienced increased mortality due to hepatic lipidosis. Some hens showed signs of dyspnea and cyanosis before death. Necropsy revealed dark muscles and enlarged livers with pale areas and numerous hemorrhages. Petechial and ecchymotic hemorrhages were also found on the abdominal fat and epicardium. Lung congestion and edema were prominent. In the heart and blood vessels, the blood was uncoagulated. Mortality was elevated for 12 days and resulted in the death of 0.7% of the turkey hens in one flock and 1.7% in the other. Vitamin E administered in water at a dose of 25 IU per hen appeared to reduce mortality. The nutritional and environmental factors that may contribute to the development of hepatic lipidosis in turkeys are discussed.

  5. Feline idiopathic hepatic lipidosis.

    Dimski, D S; Taboada, J

    1995-03-01

    Feline IHL is a severe hepatopathy that can be treated by aggressive nutritional support. Until the underlying mechanisms of protein and lipid metabolism are understood in both healthy and ill cats, dietary therapy remains supportive. It is likely that the pathogenesis of IHL in cats is multifactorial, involving both increased fatty acid mobilization to the liver and a defect in oxidation of fatty acids or removal of VLDL. It is also possible that individual variation may play a role in the development of this disease in cats undergoing starvation. Continued studies will focus on the unique pathways of hepatic metabolism in the cat, and how these pathways are altered, leading to hepatic lipid accumulation and clinical disease. Hopefully, these studies can be applied to the prevention or treatment of IHL in cats.

  6. Computed tomography in hepatic trauma

    Moon, K.L. Jr.; Federle, M.P.

    1983-01-01

    Twenty-five patients with hepatic injury from blunt upper abdominal trauma were examined by computed tomography (CT). The spectrum of CT findings was recorded, and the size of the hepatic laceration and the associated hemoperitoneum were correlated with the mode of therapy used in each case (operative vs nonoperative). While the need for surgery correlated roughly with the size of the hepatic laceration, the size of the associated hemoperitoneum was an important modifying factor. Fifteen patients with hepatic lacerations but little or no hemoperitoneum were managed nonoperatively. CT seems to have significant advantages over hepatic scintigraphy, angiography, and diagnostic peritoneal lavage. By combining inforamtion on the clinical state of the patient and CT findings, therapy of hepatic injury can be individualized and the incidence of nontherapeutic laparotomies decreased

  7. [Autoimmune hepatitis: Immunological diagnosis].

    Brahim, Imane; Brahim, Ikram; Hazime, Raja; Admou, Brahim

    2017-11-01

    Autoimmune hepatopathies (AIHT) including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune cholangitis (AIC), represent an impressive entities in clinical practice. Their pathogenesis is not perfectly elucidated. Several factors are involved in the initiation of hepatic autoimmune and inflammatory phenomena such as genetic predisposition, molecular mimicry and/or abnormalities of T-regulatory lymphocytes. AIHT have a wide spectrum of presentation, ranging from asymptomatic forms to severe acute liver failure. The diagnosis of AIHT is based on the presence of hyperglobulinemia, cytolysis, cholestasis, typical even specific circulating auto-antibodies, distinctive of AIH or PBC, and histological abnormalities as well as necrosis and inflammation. Anti-F actin, anti-LKM1, anti-LC1 antibodies permit to distinguish between AIH type 1 and AIH type 2. Anti-SLA/LP antibodies are rather associated to more severe hepatitis, and particularly useful for the diagnosis of seronegative AIH for other the antibodies. Due to the relevant diagnostic value of anti-M2, anti-Sp100, and anti-gp210 antibodies, the diagnosis of PBC is more affordable than that of PSC and AIC. Based on clinical data, the immunological diagnosis of AIHT takes advantage of the various specialized laboratory techniques including immunofluorescence, immunodot or blot, and the Elisa systems, provided of a closer collaboration between the biologist and the physician. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  8. Structure of the Zymomonas mobilis respiratory chain: oxygen affinity of electron transport and the role of cytochrome c peroxidase.

    Balodite, Elina; Strazdina, Inese; Galinina, Nina; McLean, Samantha; Rutkis, Reinis; Poole, Robert K; Kalnenieks, Uldis

    2014-09-01

    The genome of the ethanol-producing bacterium Zymomonas mobilis encodes a bd-type terminal oxidase, cytochrome bc1 complex and several c-type cytochromes, yet lacks sequences homologous to any of the known bacterial cytochrome c oxidase genes. Recently, it was suggested that a putative respiratory cytochrome c peroxidase, receiving electrons from the cytochrome bc1 complex via cytochrome c552, might function as a peroxidase and/or an alternative oxidase. The present study was designed to test this hypothesis, by construction of a cytochrome c peroxidase mutant (Zm6-perC), and comparison of its properties with those of a mutant defective in the cytochrome b subunit of the bc1 complex (Zm6-cytB). Disruption of the cytochrome c peroxidase gene (ZZ60192) caused a decrease of the membrane NADH peroxidase activity, impaired the resistance of growing culture to exogenous hydrogen peroxide and hampered aerobic growth. However, this mutation did not affect the activity or oxygen affinity of the respiratory chain, or the kinetics of cytochrome d reduction. Furthermore, the peroxide resistance and membrane NADH peroxidase activity of strain Zm6-cytB had not decreased, but both the oxygen affinity of electron transport and the kinetics of cytochrome d reduction were affected. It is therefore concluded that the cytochrome c peroxidase does not terminate the cytochrome bc1 branch of Z. mobilis, and that it is functioning as a quinol peroxidase. © 2014 The Authors.

  9. Influence of acute and chronic administration of methadone hydrochloride on NADPH-cytochrome c reductase and cytochrome P-450 of mouse liver microsomes.

    Datta, R K; Johnson, E A; Bhattacharjee, G; Stenger, R J

    1976-03-01

    Administration of a single acute dose (20 mg/kg body weight) of methadone hydrochloride to both male and female mice increased the specific activity of NADPH-cytochrome c reductase and did not change much the content of cytochrome P-450 of their liver microsomes. Administration of multiple acute doses of methadone in male mice increased the specific activity of cytochrome c reductase and the content of cytochrome P-450 of their liver microsomes. Chronic administration of progressively increasing doses of methadone (up to 40 mg/kg body weight) to male mice increased the specific activity of c reductase. Similar chronic administration of methadone up to 28 mg/kg body weight also increased the microsomal content of P-450, but with higher doses of methadone, the content of P-450 declined and finally dropped slightly below control levels. The levels of c reductase activity and P-450 content returned to normal about two weeks after discontinuation of methadone administration.

  10. A cytosolic cytochrome b 5-like protein in yeast cell accelerating the electron transfer from NADPH to cytochrome c catalyzed by Old Yellow Enzyme

    Nakagawa, Manabu; Yamano, Toshio; Kuroda, Kiyo; Nonaka, Yasuki; Tojo, Hiromasa; Fujii, Shigeru

    2005-01-01

    A 410-nm absorbing species which enhanced the reduction rate of cytochrome c by Old Yellow Enzyme (OYE) with NADPH was found in Saccharomyces cerevisiae. It was solubilized together with OYE by the treatment of yeast cells with 10% ethyl acetate. The purified species showed visible absorption spectra in both oxidized and reduced forms, which were the same as those of the yeast microsomal cytochrome b 5 . At least 14 amino acid residues of the N-terminal region coincided with those of yeast microsomal b 5 , but the protein had a lower molecular weight determined to be 12,600 by SDS-PAGE and 9775 by mass spectrometry. The cytochrome b 5 -like protein enhanced the reduction rate of cytochrome c by OYE, and a plot of the reduction rates against its concentration showed a sigmoidal curve with an inflexion point at 6 x 10 -8 M of the protein

  11. Type B Hepatitis in Iran

    M. Tabarestani

    1977-01-01

    Full Text Available Hepatitis B surface antigen CHBsAg was found in 1% of controls, 2.1% of professional blood donors, 2.0% of leprosy patients and 76.1% of acute hepatitis in Tehran and Mashhad, Iran. All HBsAg positive samples also possessed antibody to the hepatitis B core antigen and all were subtype ayw. Type B hepatitis and the HBsAg state aloe frequent in Iran, but most must be accounted for by u nonparenter- al" or "rnapparent'' parenteral exposure.

  12. Antimycin-insensitive mutants of Candida utilis II. The effects of antimycin on Cytochrome b

    Grimmelikhuijzen, C J; Marres, C A; Slater, Conor

    1975-01-01

    1. Cytochrome b-562 is more reduced in submitochondrial particles of mutant 28 during the aerobic steady-state respiration with succinate than in particles of the wild type. When anaerobiosis is reached, the reduction of cytochrome b is preceded by a rapid reoxidation in the mutnat. A similar reo...

  13. Electrochemical determination of hydrogen peroxide using Rhodobacter capsulatus cytochrome c peroxidase at a gold electrode

    De Wael, K.; Buschop, H.; Heering, H.A.; De Smet, L.; Van Beeumen, J.; Devreese, B.; Adriaens, A.

    2007-01-01

    We describe the redox behaviour of horse heart cytochrome c (HHC) and Rhodobacter capsulatus cytochrome c peroxidase (RcCCP) at a gold electrode modified with 4,4?-bipyridyl. RcCCP shows no additional oxidation or reduction peaks compared to the electrochemistry of only HHC, which indicates that it

  14. Immobilized unfolded cytochrome c acts as a catalyst for dioxygen reduction.

    Tavagnacco, Claudio; Monari, Stefano; Ranieri, Antonio; Bortolotti, Carlo Augusto; Peressini, Silvia; Borsari, Marco

    2011-10-21

    Unfolding turns immobilized cytochrome c into a His-His ligated form endowed with catalytic activity towards O(2), which is absent in the native protein. Dioxygen could be used by naturally occurring unfolded cytochrome c as a substrate for the production of partially reduced oxygen species (PROS) contributing to the cell oxidative stress.

  15. Effect of carbon source on the accumulation of cytochrome P-450 in the yeast Saccharomyces cerevisiae.

    Kärenlampi, S O; Marin, E; Hänninen, O O

    1981-02-15

    The appearance of cytochrome P-450 in the yeast Saccharomyces cerevisiae depended on the substrate supporting growth. Cytochrome P-450 was apparent in yeast cells grown on a strongly fermentable sugar such as D-glucose, D-fructose or sucrose. When yeast was grown on D-galactose, D-mannose or maltose, where fermentation and respiration occurred concomitantly, cytochrome P-450 was also formed. The cytochrome P-450 concentration was maximal at the beginning of the stationary phase of the culture. Thereafter the concentration decreased, reaching zero at a late-stationary phase. When the yeast was grown on a medium that contained lactose or pentoses (L-arabinose, L-rhamnose, D-ribose and D-xylose), cytochrome P-450 did not occur. When a non-fermentable energy source (glycerol, lactate or ethanol) was used, no cytochrome P-450 was detectable. Transfer of cells from D-glucose medium to ethanol medium caused a slow disappearance of cytochrome P-450, although the amount of the haemoprotein still continued to increase in the control cultures. Cytochrome P-450 appeared thus to accumulate in conditions where the rate of growth was fast and fermentation occurred. Occurrence of this haemoprotein is not necessarily linked, however, with the repression of mitochondrial haemoprotein synthesis.

  16. The functional localization of cytochromes b in the respiratory chain of anaerobically grown Proteus mirabilis

    Van Wielink, J E; Reijnders, W N; Van Spanning, R J; Oltmann, L F; Stouthamer, A.H.

    1986-01-01

    The functional localization of the cytochromes b found in anaerobically grown Proteus mirabilis was investigated. From light absorption spectra, scanned during uninhibited and HQNO-inhibited electron transport to various electron acceptors, it was concluded that all cytochromes b function between

  17. Induction of cytochrome P450-associated monooxygenases in northern leopard frogs, Rana pipiens, by 3,3',4,4',5-pentachlorobiphenyl

    Huang, Y.-W.; Melancon, M.J.; Jung, R.E.; Karasov, W.H.

    1998-01-01

    Northern leopard frogs (Rana pipiens) were injected intraperitoneally either with a solution of polychlorinated biphenyl (PCB) 126 in corn oil at a concentration of 0.2, 0.7, 2.3 and 7.8 mg/kg body weight or with corn oil alone. Appropriate assay conditions with hepatic microsomes were determined for four cytochrome P450-associated monooxygenases: ethoxyresorufin-O-dealkylase (EROD), methoxy-ROD (MROD), benzyloxy-ROD (BROD) and pentoxy-ROD (PROD). One week after PCB administration, the specific activities of EROD, MROD, BROD and PROD were not elevated at doses ? 0.7 mg/kg (p > 0.05), but were significantly increased at doses ? 2.3 mg/kg compared to the control groups (p leopard frogs.

  18. Hepatite E Hepatitis E

    Raymundo Paraná

    2002-06-01

    Full Text Available O vírus da hepatite E (VHE é o segundo vírus de transmissão fecal-oral com hepatotropismo confirmado, após o vírus da hepatite A. As grandes epidemias de hepatite das décadas de 50 e 60 na Índia foram causadas pelo VHE. Observaram-se surtos da infecção na África Central, América Latina, Oriente Médio e Repúblicas independentes da ex-União Soviética. O quadro clínico da doença assemelha-se ao de outras hepatites virais. Não há casos descritos de hepatite E crônicas. Cerca de 20% das mulheres que adquirem a doença durante a gravidez desenvolvem formas graves, com insuficiência hepática fulminante. Confirma-se o diagnóstico quando se encontra no soro anticorpos (método de ELISA das classes IgM (fase aguda e/ou IgG (curados. O imunoblot e o PCR-RNA podem ser usados quando necessário. Não há tratamento específico. O uso de imunoglobulina hiperimune tem sido aconselhado por alguns autores. A prevenção se faz pelos cuidados higiênicos e dietéticos habituais. Não há vacina eficaz contra a doença.Hepatitis E virus (HEV is the second most frequent hepatotropic virus transmitted via fecal-oral route, following closely behind hepatitis A virus. The great epidemics of hepatitis described during the 50s and 60s, in India, were caused by this virus. Epidemic bursts have also been described in Central Africa, Latin America, Middle East and in the independent Republics of the ex-Soviet Union. The clinical features of the disease do not differ from those reported for other viral hepatitides. There have been no cases of chronic hepatitis E reported. Around 20% of women infected during pregnancy develop a severe form of hepatitis which courses to liver failure. Diagnosis of hepatitis is confirmed when antibodies (using ELISA of the IgM class (acute phase and/or IgG (infected and cured are found in the serum. Immunoblot and PCR-RNA may be used as necessary. There is no specific treatment for hepatitis E. Hyperimmune serum has

  19. Prevalence of hepatitis B, hepatitis C and human immunodeficiency ...

    Background. Hepatitis B virus (HBV), hepatitis C virus (HCV) and HIV are common blood-borne infections unevenly distributed across regions in Nigeria. Few population-based prevalence studies have been done in Nigeria. Objective. To determine the prevalence of HBV, HCV and HIV and risk factors for infection with ...

  20. Prevention of Hepatitis B Virus and Hepatitis C Virus Transmission ...

    Introduction: Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in hemodialysis (HD) patients are associated with adverse outcomes, especially after kidney transplantation. Review: In the HD setting, cross-contamination to patients via environmental surfaces, supplies, equipment, multiple-dose medication vials ...

  1. Hepatitis B Virus, Hepatitis C Virus and Human Immunodeficiency ...

    Background: The epidemiology of viral hepatitis and Human immunodeficiency virus (HIV) during pregnancy is of great importance for health planners and program managers. However, few published data on viral hepatitis and HIV are available in Sudan especially during pregnancy. Objectives: The current study was ...

  2. Prevalence of hepatitis B surface antigen, hepatitis C and Human ...

    Objective: Human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C viruses (HCV) are major causes of mortality and morbidity worldwide. They are also among the commonest transfusiontransmissible infectious agents. Students of higher institutions are often used as voluntary unpaid donors by many ...

  3. HIV, hepatitis B, and hepatitis C in Zambia

    Kenneth C Kapembwa

    2011-01-01

    Full Text Available Objectives : Epidemiologic data of HIV and viral hepatitis coinfection are needed in sub-Saharan Africa to guide health policy for hepatitis screening and optimized antiretroviral therapy (ART. Materials and Methods: We screened 323 HIV-infected, ART-eligible adults for hepatitis B surface antigen (HBsAg and hepatitis C antibody (HCV Ab at a tertiary hospital in Lusaka, Zambia. We collected basic demographic, medical, and laboratory data to determine predictors for coinfection. Results: Of 323 enrolled patients, 32 (9.9%; 95% CI=6.7-13.2% were HBsAg positive, while 4 (1.2%; 95% CI=0.03-2.4% were HCV Ab positive. Patients with hepatitis B coinfection were more likely to be 200 IU/L was uncommon and did not differ between the two groups (3.4% vs. 2.3%; P=0.5. We were unable to determine predictors of hepatitis C infection due to the low prevalence of disease. Conclusions: HIV and hepatitis B coinfection was common among patients initiating ART at this tertiary care facility. Routine screening for hepatitis B should be considered for HIV-infected persons in southern Africa.

  4. Role of brain cytochrome P450 mono-oxygenases in bilirubin oxidation-specific induction and activity.

    Gambaro, Sabrina E; Robert, Maria C; Tiribelli, Claudio; Gazzin, Silvia

    2016-02-01

    In the Crigler-Najjar type I syndrome, the genetic absence of efficient hepatic glucuronidation of unconjugated bilirubin (UCB) by the uridine 5'-diphospho-glucuronosyltransferase1A1 (UGT1A1) enzyme produces the rise of UCB level in blood. Its entry to central nervous system could generate toxicity and neurological damage, and even death. In the past years, a compensatory mechanism to liver glucuronidation has been indicated in the hepatic cytochromes P450 enzymes (Cyps) which are able to oxidize bilirubin. Cyps are expressed also in the central nervous system, the target of bilirubin toxicity, thus making them theoretically important to confer a protective activity toward bilirubin accumulation and neurotoxicity. We therefore investigated the functional induction (mRNA, EROD/MROD) and the ability to oxidize bilirubin of Cyp1A1, 1A2, and 2A3 in primary astrocytes cultures obtained from two rat brain region (cortex: Cx and cerebellum: Cll). We observed that Cyp1A1 was the Cyp isoform more easily induced by beta-naphtoflavone (βNF) in both Cx and Cll astrocytes, but oxidized bilirubin only after uncoupling by 3, 4,3',4'-tetrachlorobiphenyl (TCB). On the contrary, Cyp1A2 was the most active Cyp in bilirubin clearance without uncoupling, but its induction was confined only in Cx cells. Brain Cyp2A3 was not inducible. In conclusion, the exposure of astrocytes to βNF plus TCB significantly enhanced Cyp1A1 mediating bilirubin clearance, improving cell viability in both regions. These results may be a relevant groundwork for the manipulation of brain Cyps as a therapeutic approach in reducing bilirubin-induced neurological damage.

  5. Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy.

    Mast, Natalia; Lin, Joseph B; Pikuleva, Irina A

    2015-09-01

    Cytochrome P450 CYP27A1 is the only enzyme in humans converting cholesterol to 27-hydroxycholesterol, an oxysterol of multiple functions, including tissue-specific modulation of estrogen and liver X receptors. Both receptors seem to mediate adverse effects of 27-hydroxycholesterol in breast cancer when the levels of this oxysterol are elevated. The present work assessed druggability of CYP27A1 as a potential antibreast cancer target. We selected 26 anticancer and noncancer medications, most approved by the Food and Drug Administration, and evaluated them first in vitro for inhibition of purified recombinant CYP27A1 and binding to the enzyme active site. Six strong CYP27A1 inhibitors/binders were identified. These were the two antibreast cancer pharmaceuticals anastrozole and fadrozole, antiprostate cancer drug bicalutamide, sedative dexmedetomidine, and two antifungals ravuconazole and posaconazole. Anastrozole was then tested in vivo on mice, which received subcutaneous drug injections for 1 week. Mouse plasma and hepatic 27-hydroxycholesterol levels were decreased 2.6- and 1.6-fold, respectively, whereas plasma and hepatic cholesterol content remained unchanged. Thus, pharmacologic CYP27A1 inhibition is possible in the whole body and individual organs, but does not negatively affect cholesterol elimination. Our results enhance the potential of CYP27A1 as an antibreast cancer target, could be of importance for the interpretation of Femara versus Anastrozole Clinical Evaluation Trial, and bring attention to posaconazole as a potential complementary anti-breast cancer medication. More medications on the US market may have unanticipated off-target inhibition of CYP27A1, and we propose strategies for their identification. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  6. Induced cytochrome P450 1A activity in cichlid fishes from Guandu River and Jacarepaguá Lake, Rio de Janeiro, Brazil.

    Parente, Thiago E M; De-Oliveira, Ana C A X; Paumgartten, Francisco J R

    2008-03-01

    The induction of cytochrome P4501A-mediated activity (e.g. ethoxyresorufin-O-deethylation, EROD) has been used as a biomarker for monitoring fish exposure to AhR-receptor ligands such as polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB) and polychlorinated dibenzo-dioxins/furans (PCDD/Fs). In this study we found that hepatic EROD is induced in fish ("Nile tilapia", Oreochromis niloticus and "acará", Geophagus brasiliensis) from the Guandu River (7-17-fold) and Jacarepaguá Lake (7-fold), Rio de Janeiro, Brazil. Since both cichlid fish are consumed by the local population and the Guandu River is the main source of the drinking water supply for the greater Rio de Janeiro metropolitan area, pollution by cytochrome P4501A-inducing chemicals is a cause for concern and should be further investigated in sediments, water and biota. We additionally showed that EROD activity in the fish liver post-mitochondrial supernatant-simpler, cheaper and less time consuming to prepare than the microsomal fraction-is sufficiently sensitive for monitoring purposes.

  7. Effectiveness of cytochrome C and cepharanthin for leukopenia following multidisciplinary treatment

    Tabata, Kumiko; Endow, Masaru; Suzuki, Hirotoshi

    1986-01-01

    Leukopenia is one of important problems for multidisciplinary treatment of malignant tumor. We could not be able to take a continuous cancer therapy because of leukopenia. And then we had a study of effectiveness combination treatment of cytochrome C with cepharanthin for leukopenia of cancer patient. We carried on the study of 3 classifications of treatment as follows, a) cytochrome C only, b) combined cytochrome C with cepharanthin, and c) control group without drugs. Bone marrow potentiality is individual differentiation and then the group was administrated both cytochrome C and cepharanthin following radiotherapy associated with postoperative breast cancer. The above description lead to conclusion that combination treatment of cytochrome C and cepharanthin was available for protective drugs from multidisciplinary treatment induced leukemia. (author)

  8. Acrolein, A Reactive Product of Lipid Peroxidation, Induces Oxidative Modification of Cytochrome c

    Kang, Jung Hoon [Cheongju Univ., Cheongju (Korea, Republic of)

    2013-11-15

    Acrolein (ACR) is a well-known carbonyl toxin produced by lipid peroxidation of polyunsaturated fatty acids, which is involved in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). In Alzheimer's brain, ACR was found to be elevated in hippocampus and temporal cortex where oxidative stress is high. In this study, we evaluated oxidative modification of cytochrome c occurring after incubation with ACR. When cytochrome c was incubated with ACR, protein aggregation increased in a dose-dependent manner. The formation of carbonyl compounds and the release of iron were obtained in ACR-treated cytochrome c. Reactive oxygen species scavengers and iron specific chelator inhibited the ACR-mediated cytochrome c modification and carbonyl compound formation. Our data demonstrate that oxidative damage of cytochrome c by ACR might induce disruption of cyotochrome c structure and iron mishandling as a contributing factor to the pathology of AD.

  9. Acrolein, A Reactive Product of Lipid Peroxidation, Induces Oxidative Modification of Cytochrome c

    Kang, Jung Hoon

    2013-01-01

    Acrolein (ACR) is a well-known carbonyl toxin produced by lipid peroxidation of polyunsaturated fatty acids, which is involved in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). In Alzheimer's brain, ACR was found to be elevated in hippocampus and temporal cortex where oxidative stress is high. In this study, we evaluated oxidative modification of cytochrome c occurring after incubation with ACR. When cytochrome c was incubated with ACR, protein aggregation increased in a dose-dependent manner. The formation of carbonyl compounds and the release of iron were obtained in ACR-treated cytochrome c. Reactive oxygen species scavengers and iron specific chelator inhibited the ACR-mediated cytochrome c modification and carbonyl compound formation. Our data demonstrate that oxidative damage of cytochrome c by ACR might induce disruption of cyotochrome c structure and iron mishandling as a contributing factor to the pathology of AD

  10. Cytochromes c': Structure, Reactivity and Relevance to Haem-Based Gas Sensing.

    Hough, Michael A; Andrew, Colin R

    2015-01-01

    Cytochromes c' are a group of class IIa cytochromes with pentacoordinate haem centres and are found in photosynthetic, denitrifying and methanotrophic bacteria. Their function remains unclear, although roles in nitric oxide (NO) trafficking during denitrification or in cellular defence against nitrosoative stress have been proposed. Cytochromes c' are typically dimeric with each c-type haem-containing monomer folding as a four-α-helix bundle. Their hydrophobic and crowded distal sites impose severe restrictions on the binding of distal ligands, including diatomic gases. By contrast, NO binds to the proximal haem face in a similar manner to that of the eukaryotic NO sensor, soluble guanylate cyclase and bacterial analogues. In this review, we focus on how structural features of cytochromes c' influence haem spectroscopy and reactivity with NO, CO and O2. We also discuss the relevance of cytochrome c' to understanding the mechanisms of gas binding to haem-based sensor proteins. © 2015 Elsevier Ltd. All rights reserved.

  11. Cytochrome c and c1 heme lyases are essential in Plasmodium berghei.

    Posayapisit, Navaporn; Songsungthong, Warangkhana; Koonyosying, Pongpisid; Falade, Mofolusho O; Uthaipibull, Chairat; Yuthavong, Yongyuth; Shaw, Philip J; Kamchonwongpaisan, Sumalee

    Malaria parasites possess a de novo heme synthetic pathway. Interestingly, this pathway is dispensable during the blood stages of development in mammalian hosts. The assembly of the two most important hemeproteins, cytochromes c and c1, is mediated by cytochrome heme lyase enzymes. Plasmodium spp. possess two cytochrome heme lyases encoded by separate genes. Given the redundancy of heme synthesis, we sought to determine if heme lyase function also exhibits redundancy. To answer this question, we performed gene knockout experiments. We found that the PBANKA_143950 and PBANKA_0602600 Plasmodium berghei genes encoding cytochrome c (Pbcchl) and cytochrome c1 (Pbcc 1 hl) heme lyases, respectively, can only be disrupted when a complementary gene is present. In contrast, four genes in the de novo heme synthesis pathway can be disrupted without complementation. This work provides evidence that Pbcchl and Pbcc 1 hl are both essential and thus may be antimalarial targets. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Tiamulin selectively inhibits oxidative hepatic steroid and drug metabolism in vitro in the pig.

    Witkamp, R F; Nijmeijer, S M; Csikó, G; van Miert, A S

    1994-08-01

    The simultaneous use of the antibiotic tiamulin with certain ionophoric antibiotics (monensin, salinomycin) may give rise to a toxic interaction in pigs and poultry. In the present study, effects of tiamulin on hepatic cytochrome P450 activities in vitro were studied using pig liver microsomes. When tiamulin was added to the incubation medium the N-demethylation rate of ethylmorphine and the hydroxylation of testosterone at the 6 beta- and 11 alpha-positions was strongly inhibited. Tiamulin inhibited these activities more than SKF525A or cimetidine, but less than ketoconazole. The microsomal N-demethylation rate of erythromycin and the hydroxylation of testosterone at the 2 beta-position were inhibited to a lesser degree, whereas the ethoxyresorufin-O-deethylation, aniline hydroxylation and testosterone hydroxylations at the 15 alpha- and 15 beta-positions were not affected by tiamulin. No in vitro complexation by tiamulin of cytochrome P450 resulting in a loss of CO-binding capacity could be demonstrated. Results from the present study suggest a selective inhibition of cytochrome P450 enzymes in pigs, probably belonging to the P4503A subfamily. The mechanism of this interaction is still unclear. However, interactions between tiamulin and those veterinary drugs or endogenous compounds which undergo oxidative metabolism by P450 enzymes must be considered. More research is needed to reveal which of the P450 enzymes are affected by tiamulin in order to improve the understanding and probably the predictability of this interaction.

  13. Esculetin Ameliorates Carbon Tetrachloride-Mediated Hepatic Apoptosis in Rats

    Chuan-Sung Chiu

    2011-06-01

    Full Text Available Esculetin (ESC is a coumarin that is present in several plants such as Fraxinus rhynchophylla and Artemisia capillaris. Our previous study found that FR ethanol extract (FREtOH significantly ameliorated rats’ liver function. This study was intended to investigate the protective mechanism of ESC in hepatic apoptosis in rats induced by carbon tetrachloride. Rat hepatic apoptosis was induced by oral administration of CCl4. All rats were administered orally with CCl4 (20%, 0.5 mL/rat twice a week for 8 weeks. Rats in the ESC groups were treated daily with ESC, and silymarin group were treated daily with silymarin. Serum alanine aminotransferase (ALT, aspartate aminotransferase (AST as well as the activities of the anti-oxidative enzymes glutathione peroxidase (GPx, superoxide dismutase (SOD, and catalase in the liver were measured. In addition, expression of liver apoptosis proteins and anti-apoptotic proteins were detected. ESC (100, 500 mg/kg significantly reduced the elevated activities of serum ALT and AST caused by CCl4 and significantly increased the activities of catalase, GPx and SOD. Furthermore, ESC (100, 500 mg/kg significantly decreased the levels of the proapoptotic proteins (t-Bid, Bak and Bad and significantly increased the levels of the anti-apoptotic proteins (Bcl-2 and Bcl-xL. ESC inhibited the release of cytochrome c from mitochondria. In addition, the levels of activated caspase-9 and activated caspase-3 were significantly decreased in rats treated with ESC than those in rats treated with CCl4 alone. ESC significantly reduced CCl4-induced hepatic apoptosis in rats.

  14. Aspiration sclerotherapy of hepatic cysts

    Wijnands, T.F.M.

    2017-01-01

    Hepatic cysts are fluid-filled lesions in the liver that generally arise as congenital anomalies. Prevalence is estimated between 3 and 18%. Overall, cysts are benign and asymptomatic. However, hepatic cysts can increase to a volume of several liters as a result of continuous fluid production by the

  15. Blood transfusion and hepatitis viruses

    virus in blood donors: investigation of type-specific differences in serologic reactivity and rate of alanine aminotransferase abnormalities. Transfusion 1993;. 33: 7-13. 45. McFarlane IG, Smith HM, Johnson PJ, Bray GP, Vergani 0, Williams R. Hepatitis. C virus antibodies in chronic active hepatitis: pathogenetic factor or false-.

  16. Hepatitis B vaccination in travelers

    Sonder, Gerard J. B.

    2008-01-01

    An increasing number of travelers travel to hepatitis B-endemic countries. In travel medicine, vaccinations should be advised according to risks. The actual incidence of hepatitis B infection in short-term tourists is very low and probably not higher than it is for people who do not travel. There is

  17. Screening of subclinical hepatic encephalopathy

    Groeneweg, M; Moerland, W; Quero, J C; Hop, W C; Krabbe, P F; Schalm, S W

    BACKGROUND/AIMS: Subclinical hepatic encephalopathy adversely affects daily functioning. The aim of this study was to determine which elements of daily life have predictive value for subclinical hepatic encephalopathy. METHODS: The study was performed in 179 outpatients with liver cirrhosis.

  18. Hepatitis B and skin: review

    Zonunsanga

    2015-01-01

    Full Text Available Hepatitis B virus (HBV infection and its complications have become a global health problem. The spectrum of HBV infection ranges from asymptomatic carrier state to chronic hepatitis. It is usually preceded by constitutional symptoms. It has a wide range of dermatological manifestations. This review includes the pathogenesis along with the pathophysiology with their clinical significance and overview of the treatment.

  19. Bile acids for viral hepatitis

    Chen, Weikeng; Liu, J; Gluud, C

    2003-01-01

    The viral hepatitides are common causes of liver diseases globally. Trials have assessed bile acids for patients with viral hepatitis, but no consensus was reached regarding their usefulness.......The viral hepatitides are common causes of liver diseases globally. Trials have assessed bile acids for patients with viral hepatitis, but no consensus was reached regarding their usefulness....

  20. Hepatic Lipodystrophy in Galloway Calves.

    Wieland, M; Mann, S; Hafner-Marx, A; Ignatius, A; Metzner, M

    2017-05-01

    Hepatic lipodystrophy in Galloway calves is a fatal liver disease affecting a small proportion of the Galloway breed described in different parts of Europe and North America during the past decades. The clinical findings include a diversity of neurological signs. Clinical pathology findings frequently indicate hepatobiliary disease. Postmortem examination reveals an enlarged, pale yellow, and firm liver. Histologic lesions include hepatic fibrosis, hepatic lipidosis, and bile duct hyperplasia. To date, the etiopathogenesis remains obscure. Infectious causes, intoxications, and a hereditary origin have been considered. We describe hepatic lipodystrophy in Galloway calves from an extensively farmed cow-calf operation in southern Germany. Main clinical findings in 6 calves were consistent with hepatic encephalopathy. Clinical pathology findings in 5 of 6 tested animals revealed increased concentration of total bilirubin (maximum value [MV], 54 μmol/l; reference range [RR], 250 U/g Hb). Postmortem examination in 6 calves revealed a firm, diffusely enlarged yellow liver with a finely nodular surface. Histologic lesions included hepatic fibrosis, hepatic lipidosis, and bile duct hyperplasia. Our findings add to the existing data on hepatic lipodystrophy in the Galloway breed and outline a protocol to aid in the diagnosis of this disorder.

  1. Autoimmune hepatitis vs. pregnancy

    Olga Adamczyk-Gruszka

    2017-07-01

    Full Text Available Introduction Autoimmune hepatitis (AIH is a disease of unknown etiology. In pregnancy, it may have mild clinical course as well as can lead to liver failure, or exacerbation of clinical symptoms. In pregnant women the severity of symptoms is often observed between the second and third trimester, and in the puerperium. The disease is marked by enhanced activity of Th lymphocytes, which hepatocytes recognize as foreign antigens. This results in interleukin production activating B lymphocytes, and the production of specific antibodies attacking and destroying the hepatocytes. Case report A 35-year old patient, CII PII, 7 Hbd, with autoimmune hepatitis reported for a check-up. Her first pregnancy was 18 years ago, without history of underlying disease, carried to term without complications. The woman gave birth to a baby-son weighing 3,280g, 10 points Apgar. The delivery was spontaneous and uneventful. The patient got pregnant after an 18-year break. When she twice-tested positively for pregnancy, the treatment with azathioprine was switched to prednisolone. Over the pregnancy the patient was hospitalized 4 times, in 25, 29, 35, and 37 week of gestation due to a threat of preterm delivery, and pregnancy-related cholestasis associated with AIH. In 37 week of gestation, delivery was induced, and she gave birth to a healthy male, weighing 2,650 g, body height of 49 cm, 10 points Apgar scale. The liver function improved and stabilized after the delivery. Treatment with prednisolone has been continued, and the patient’s condition is still controlled. Pregnant patients with autoimmune hepatitis often experience exacerbation of the disease, especially in the third trimester, and in the postpartum period. This case shows that with proper care it is possible to continue and terminate pregnancy safely for the mother and her newly born baby.

  2. The production of ammonia by multiheme cytochromes C.

    Simon, Jörg; Kroneck, Peter M H

    2014-01-01

    The global biogeochemical nitrogen cycle is essential for life on Earth. Many of the underlying biotic reactions are catalyzed by a multitude of prokaryotic and eukaryotic life forms whereas others are exclusively carried out by microorganisms. The last century has seen the rise of a dramatic imbalance in the global nitrogen cycle due to human behavior that was mainly caused by the invention of the Haber-Bosch process. Its main product, ammonia, is a chemically reactive and biotically favorable form of bound nitrogen. The anthropogenic supply of reduced nitrogen to the biosphere in the form of ammonia, for example during environmental fertilization, livestock farming, and industrial processes, is mandatory in feeding an increasing world population. In this chapter, environmental ammonia pollution is linked to the activity of microbial metalloenzymes involved in respiratory energy metabolism and bioenergetics. Ammonia-producing multiheme cytochromes c are discussed as paradigm enzymes.

  3. The Membrane Modulates Internal Proton Transfer in Cytochrome c Oxidase

    Öjemyr, Linda Nasvik; Ballmoos, Christoph von; Faxén, Kristina

    2012-01-01

    The functionality of membrane proteins is often modulated by the surrounding membrane. Here, we investigated the effect of membrane reconstitution of purified cytochrome c oxidase (CytcO) on the kinetics and thermodynamics of internal electron and proton-transfer reactions during O-2 reduction...... DOPC lipids. In conclusion, the data show that the membrane significantly modulates internal charge-transfer reactions and thereby the function of the membrane-bound enzyme.......-glycerol) (DOPG). In addition, a small Change in the internal Cu-A-heme a electron equilibrium constant was observed. This effect was lipid-dependent and explained in terms of a lower electrostatic potential within the membrane-spanning part of the protein with the anionic DOPG lipids than with the zwitterionic...

  4. Cytochrome P450 polymorphism and postoperative cognitive dysfunction

    Steinmetz, J; Jespersgaard, Cathrine; Dalhoff, Kim Peder

    2012-01-01

    neuropsychological testing at one week had POCD, and 24 out of 307 (7.8%) had POCD at three months. None of the examined CYP2C19, 2D6 alleles, or various phenotypes were significantly associated with POCD. CONCLUSION: Polymorphisms in CYP2C19, or 2D6 genes do not seem to be related to the occurrence of cognitive......BACKGROUND:The etiology of postoperative cognitive dysfunction (POCD) remains unclear but toxicity of anesthetic drugs and their metabolites could be important. We aimed to assess the possible association between POCD after propofol anesthesia and various phenotypes owing to polymorphisms...... in cytochrome P450 encoding genes. METHODS:We included patients who underwent non-cardiac surgery under total intravenous anesthesia with propofol. POCD was identified using a neuropsychological test-battery administered preoperatively, one week, and three months after surgery. Genotyping of CYP2C19*2, *3, CYP2...

  5. Advances in molecular modeling of human cytochrome P450 polymorphism.

    Martiny, Virginie Y; Miteva, Maria A

    2013-11-01

    Cytochrome P450 (CYP) is a supergene family of metabolizing enzymes involved in the phase I metabolism of drugs and endogenous compounds. CYP oxidation often leads to inactive drug metabolites or to highly toxic or carcinogenic metabolites involved in adverse drug reactions (ADR). During the last decade, the impact of CYP polymorphism in various drug responses and ADR has been demonstrated. Of the drugs involved in ADR, 56% are metabolized by polymorphic phase I metabolizing enzymes, 86% among them being CYP. Here, we review the major CYP polymorphic forms, their impact for drug response and current advances in molecular modeling of CYP polymorphism. We focus on recent studies exploring CYP polymorphism performed by the use of sequence-based and/or protein-structure-based computational approaches. The importance of understanding the molecular mechanisms related to CYP polymorphism and drug response at the atomic level is outlined. © 2013.

  6. Differentially regulated NADPH: cytochrome p450 oxidoreductases in parsely

    Koopmann, E.; Hahlbrock, K.

    1997-01-01

    Two NADPH:cytochrome P450 oxidoreductases (CPRs) from parsley (Petroselinum crispum) were cloned, and the complete proteins were expressed and functionally identified in yeast. The two enzymes, designated CPR1 and CPR2, are 80% identical in amino acid sequence with one another and about 75% identical with CPRs from several other plant species. The mRNA accumulation patterns for CPR1 and CPR2 in fungal elicitor-treated or UV-irradiated cultured parsley cells and in developing or infected parsley plants were compared with those for cinnamate 4-hydroxylase (C4H), one of the most abundant CPR-dependent P450 enzymes in plants. All treatments strongly induced the mRNAs for C4H and CPR1 but not for CPR2, suggesting distinct metabolic roles of CPR1 and CPR2 and a functional relationship between CPR1 and C4H

  7. Stability enhancement of cytochrome c through heme deprotonation and mutations

    Sonoyama, Takafumi; Hasegawa, Jun; Uchiyama, Susumu; Nakamura, Shota; Kobayashi, Yuji; Sambongi, Yoshihiro

    2009-01-01

    The chemical denaturation of Pseudomonas aeruginosa cytochrome c551 variants was examined at pH 5.0 and 3.6. All variants were stabilized at both pHs compared with the wild-type. Remarkably, the variants carrying the F34Y and/or E43Y mutations were more stabilized than those having the F7A/V13M or V78I ones at pH 5.0 compared with at pH 3.6 by ~3.0 – 4.6 kJ/mol. Structural analyses predicted that the side chains of introduced Tyr-34 and Tyr-43 become hydrogen donors for the hydrogen bond form...

  8. Ligand Access Channels in Cytochrome P450 Enzymes: A Review

    Philippe Urban

    2018-05-01

    Full Text Available Quantitative structure-activity relationships may bring invaluable information on structural elements of both enzymes and substrates that, together, govern substrate specificity. Buried active sites in cytochrome P450 enzymes are connected to the solvent by a network of channels exiting at the distal surface of the protein. This review presents different in silico tools that were developed to uncover such channels in P450 crystal structures. It also lists some of the experimental evidence that actually suggest that these predicted channels might indeed play a critical role in modulating P450 functions. Amino acid residues at the entrance of the channels may participate to a first global ligand recognition of ligands by P450 enzymes before they reach the buried active site. Moreover, different P450 enzymes show different networks of predicted channels. The plasticity of P450 structures is also important to take into account when looking at how channels might play their role.

  9. Hepatic metabolism affects the atropselective disposition of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) in mice.

    Wu, Xianai; Barnhart, Christopher; Lein, Pamela J; Lehmler, Hans-Joachim

    2015-01-06

    To understand the role of hepatic vs extrahepatic metabolism in the disposition of chiral PCBs, we studied the disposition of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) and its hydroxylated metabolites (HO-PCBs) in mice with defective hepatic metabolism due to the liver-specific deletion of cytochrome P450 oxidoreductase (KO mice). Female KO and congenic wild type (WT) mice were treated with racemic PCB 136, and levels and chiral signatures of PCB 136 and HO-PCBs were determined in tissues and excreta 3 days after PCB administration. PCB 136 tissue levels were higher in KO compared to WT mice. Feces was a major route of PCB metabolite excretion, with 2,2',3,3',6,6'-hexachlorobiphenyl-5-ol being the major metabolite recovered from feces. (+)-PCB 136, the second eluting PCB 136 atropisomers, was enriched in all tissues and excreta. The second eluting atropisomers of the HO-PCBs metabolites were enriched in blood and liver; 2,2',3,3',6,6'-hexachlorobiphenyl-5-ol in blood was an exception and displayed an enrichment of the first eluting atropisomers. Fecal HO-PCB levels and chiral signatures changed with time and differed between KO and WT mice, with larger HO-PCB enantiomeric fractions in WT compared to KO mice. Our results demonstrate that hepatic and, possibly, extrahepatic cytochrome P450 (P450) enzymes play a role in the disposition of PCBs.

  10. Acute Alcoholic Hepatitis: Therapy.

    Phillips, Paulina K; Lucey, Michael R

    2016-08-01

    Alcoholic hepatitis (AH) causes great morbidity and mortality in the United States and throughout the world. Advances in therapy have proven difficult. In part, this reflects challenges in diagnosis, including the distinction between AH and acute-on-chronic liver failure. Liver biopsy is the best method to clarify the cause in circumstances whereby conflicting clinical data confound the diagnosis. All treatment of AH begins with abstinence from alcohol. All patients with AH should be given sufficient nutrition. Prednisolone has become the principal agent for treating patients with severe AH. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Right hepatic artery aneurysm.

    Bernal, Astrid Del Pilar Ardila; Loures, Paulo; Calle, Juan Cristóbal Ospina; Cunha, Beatriz; Córdoba, Juan Camilo

    2016-01-01

    We report a case of an aneurysm of the right hepatic artery and its multidisciplinary management by general surgery, endoscopy and radiology services. Being a case of extremely low incidence, it is important to show its diagnostic and therapeutic approach. RESUMO Relatamos um caso de aneurisma da artéria hepática direita conduzido de forma multidisciplinar pelos Serviços de Cirurgia Geral, Endoscopia e Radiologia. Em se tratando de caso de incidência baixíssima, é importante mostrar o enfoque diagnóstico e terapêutico usado em seu manejo.

  12. HEPATITIS ALOINMUNE FETAL

    Fernando Álvarez C., Dr.

    2015-07-01

    Full Text Available La hepatitis aloinmune fetal, conocida anteriormente como hemocromatosis neonatal, ha demostrado en los últimos años ser una enfermedad completamente distinta a la hemocromatosis del adulto, tanto en su etiología como en su la fisiopatología. Este conocimiento abre nuevas perspectivas tanto en la prevención de la enfermedad en futuros embarazos, así como en el tratamiento con inmunoglobulina endovenosa en la madre durante el embarazo y eventualmente el tratamiento postnatal, en el que el trasplante de hígado juega un rol primordial.

  13. [Repeat hepatic resections].

    Popescu, I; Ciurea, S; Braşoveanu, V; Pietrăreanu, D; Tulbure, D; Georgescu, S; Stănescu, D; Herlea, V

    1998-01-01

    Five cases of iterative liver resections are presented, out of a total of 150 hepatectomies performed between 1.01.1995-1.01.1998. The resections were carried out for recurrent adenoma (one case), cholangiocarcinoma (two cases), hepatocellular carcinoma (one case), colo-rectal cancer metastasis (one case). Only cases with at least one major hepatic resection were included. Re-resections were more difficult than the primary resection due, first of all, to the modified vascular anatomy. Intraoperative ultrasound permitted localization of intrahepatic recurrences. Iterative liver resection appears to be the best therapeutical choice for patients with recurrent liver tumors.

  14. Prognostic relevance of cytochrome C oxidase in primary glioblastoma multiforme.

    Corinne E Griguer

    Full Text Available Patients with primary glioblastoma multiforme (GBM have one of the lowest overall survival rates among cancer patients, and reliable biomarkers are necessary to predict patient outcome. Cytochrome c oxidase (CcO promotes the switch from glycolytic to OXPHOS metabolism, and increased CcO activity in tumors has been associated with tumor progression after chemotherapy failure. Thus, we investigated the relationship between tumor CcO activity and the survival of patients diagnosed with primary GBM. A total of 84 patients with grade IV glioma were evaluated in this retrospective cohort study. Cumulative survival was calculated by the Kaplan-Meier method and analyzed by the log-rank test, and univariate and multivariate analyses were performed with the Cox regression model. Mitochondrial CcO activity was determined by spectrophotometrically measuring the oxidation of cytochrome c. High CcO activity was detected in a subset of glioma tumors (∼30%, and was an independent prognostic factor for shorter progression-free survival and overall survival [P = 0.0087 by the log-rank test, hazard ratio = 3.57 for progression-free survival; P<0.001 by the log-rank test, hazard ratio = 10.75 for overall survival]. The median survival time for patients with low tumor CcO activity was 14.3 months, compared with 6.3 months for patients with high tumor CcO activity. High CcO activity occurs in a significant subset of high-grade glioma patients and is an independent predictor of poor outcome. Thus, CcO activity may serve as a useful molecular marker for the categorization and targeted therapy of GBMs.

  15. Mode of Antifungal Drugs Interaction with Cytochrome P- 450

    M- Mahmodian

    1991-07-01

    Full Text Available Computer was used to identify the interactions of substrates and antifungal drugs with the enzyme, Cytochrome P-450; and then Molplot.bas computer program was applied to get three dimensional figures of 5-hydroxy camphor.oxidation products of camphor analogues, and antifungal drugs.Cartesian characteristics of atoms building molecules, are taken from Buildz. for program, which can calculate X,Y,Z coordinates of atoms by Zmatrix data. The other program which can calculate X,Y,Z coordinates, using fractional characteristics, is the Coord, for program that, gives our cartesian characteristics of the atoms of molecule, then by using these data, we obtain three dimensional figures and distance between active atoms in compounds under consideration. Results show that distance between two oxygen atoms in 5-exo-hydroxy- camphor and the other compounds obtained from oxidation of camphor analogues, with the distance of two oxygen atoms in antifungal compounds under discussion are equal. Therefore, we can conclude that, the antifungal molecule also interacts with enzyme's active site, by its own sites, in a similar manner to the 5-hydroxy camphor molecule, which is:"n1. Nitrogen atom (N of Imidazole and Triazole ring in antifungal molecule with Iron atom in heam molecule belonging to Cytochrome P-450 enzyme, are coordinated."n2. The other atoms such as : 0,S or N in structure of the antifungal drug are coordinated with hydrogen atom of hydroxyl group belong ing to Tyr-96 in the structure of enzyme, forming hydrogen bonding.

  16. Current topics in autoimmune hepatitis.

    Muratori, Luigi; Muratori, Paolo; Granito, Alessandro; Pappas, Giorgios; Cassani, Fabio; Lenzi, Marco

    2010-11-01

    Autoimmune hepatitis is a chronic liver disease of unknown aetiology characterized by interface hepatitis, hypergammaglobulinaemia and circulating autoantibodies. In the last decade a number of advancements have been made in the field of clinical and basic research: the simplified diagnostic criteria, the complete response defined as normalization of transaminase levels, the molecular identification of the antigenic targets of anti-liver cytosol antibody type 1 and anti-soluble liver antigen, the detection of anti-actin antibodies, the description of de novo autoimmune hepatitis after liver transplantation for non-autoimmune liver diseases, the characterization of autoimmune hepatitis with overlapping features of primary biliary cirrhosis or primary sclerosing cholangitis, the preliminary experience with novel treatment strategies based on cyclosporine, mycophenolate mofetil and budesonide, the role played by "impaired" regulatory T cells and the development of novel animal models of autoimmune hepatitis. Copyright © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  17. Resonance Raman study on photoreduction of cytochrome c oxidase: distinction of cytochromes a and a3 in the intermediate oxidation states.

    Ogura, T; Yoshikawa, S; Kitagawa, T

    1985-12-17

    Occurrence of photoreduction of bovine cytochrome c oxidase was confirmed with the difference absorption spectra and oxygen consumption measurements for the enzyme irradiated with laser light at 406.7, 441.6, and 590 nm. The resonance Raman spectra were obtained under the same experimental conditions as those adopted for the measurements of oxygen consumption and difference absorption spectra. The photoreduction was more effective upon irradiation at shorter wavelengths and was irreversible under anaerobic conditions. However, upon aeration into the cell, the original oxidized form was restored. It was found that aerobic laser irradiation produces a photo steady state of the catalytic dioxygen reduction and that the Raman scattering from this photo steady state probes cytochrome a2+ and cytochrome a3(3)+ separately upon excitations at 441.6 and 406.7 nm, respectively. The enzyme was apparently protected from the photoreduction in the spinning cell with the spinning speed between 1 and 1500 rpm. These results were explained satisfactorily with the reported rate constant for the electron transfer from cytochrome a to cytochrome a3 (0.58 s-1) and a comparable photoreduction rate of cytochrome a. The anaerobic photoreduction did give Raman lines at 1666 and 214 cm-1, which are characteristic of the ferrous high-spin cytochrome a3(2)+, but they were absent under aerobic photoreduction. The formyl CH = O stretching mode of the a3 heme was observed at 1671 cm-1 for a2+a3(2)+CO but at 1664 cm-1 for a2+a3(2)+CN-, indicating that the CH = O stretching frequency reflects the pi back-donation to the axial ligand similar to the oxidation state marker line (v4).

  18. Effects of aqueous extract of Ruta graveolens and its ingredients on cytochrome P450, uridine diphosphate (UDP-glucuronosyltransferase, and reduced nicotinamide adenine dinucleotide (phosphate (NAD(PH-quinone oxidoreductase in mice

    Yune-Fang Ueng

    2015-09-01

    Full Text Available Ruta graveolens (the common rue has been used for various therapeutic purposes, including relief of rheumatism and treatment of circulatory disorder. To elucidate the effects of rue on main drug-metabolizing enzymes, effects of an aqueous extract of the aerial part of rue and its ingredients on cytochrome P450 (P450/CYP, uridine diphosphate (UDP-glucuronosyltransferase, and reduced nicotinamide adenine dinucleotide (phosphate (NAD(PH:quinone oxidoreductase were studied in C57BL/6JNarl mice. Oral administration of rue extract to males increased hepatic Cyp1a and Cyp2b activities in a dose-dependent manner. Under a 7-day treatment regimen, rue extract (0.5 g/kg induced hepatic Cyp1a and Cyp2b activities and protein levels in males and females. This treatment increased hepatic UDP-glucuronosyltransferase activity only in males. However, NAD(PH:quinone oxidoreductase activity remained unchanged. Based on the contents of rutin and furanocoumarins of mouse dose of rue extract, rutin increased hepatic Cyp1a activity and the mixture of furanocoumarins (Fmix increased Cyp2b activities in males. The mixture of rutin and Fmix increased Cyp1a and Cyp2b activities. These results revealed that rutin and Fmix contributed at least in part to the P450 induction by rue.

  19. Peracute Infectious Canine Hepatitis

    A. H. Cheema*, I. Ahmed, G. Mustafa and A. Aslam

    2012-05-01

    Full Text Available Peracute infectious canine hepatitis (ICH was diagnosed in two young male dogs out of 56 dead canines presented for necropsy examination during the period of April 2009 to June 2010. These dogs were purebred, one- month old Alsatian and 5-month old Labrador. None of the dogs had received any vaccination or deworming treatment; both had died after illness lasting for six hours and twenty four hours respectively. The dogs had shown signs of depression, anorexia and fever. At necropsy, lymph nodes were swollen, edematous and congested; livers were enlarged, bright red and mottled with numerous small white foci. Petechial hemorrhages were seen in the mucosa. Excessive serosanguinous fluid was present in the abdominal cavities. Histologically, the most significant lesion was necrohemorrhagic hepatitis with single cell necrosis of hepatocytes, lacunose dilation of sinusoids filled with blood and numerous large, solid intranuclear inclusion bodies (IIBs in the hepatocytes and macrophages. Both eosinophilic and basophilic (amphophilic inclusions were seen. It has been observed that ICH is re-emerging in some endemic countries. Pet dogs should be regularly protected by effective vaccination.

  20. Perinatal hepatitis B virus detection by hepatitis B virus-DNA analysis.

    De Virgiliis, S; Frau, F; Sanna, G; Turco, M P; Figus, A L; Cornacchia, G; Cao, A

    1985-01-01

    Maternal transmission of hepatitis B virus infection in relation to the hepatitis B e antigen/antibody system and serum hepatitis B virus-DNA were evaluated. Results indicate that hepatitis B virus-DNA analysis can identify hepatitis B serum antigen positive mothers who may transmit infection to their offspring.

  1. Hepatitis C: Information on Testing and Diagnosis

    ... is a serious liver disease that results from infection with the Hepatitis C virus. Hepatitis C has been called a silent disease ... know it. Some people who get infected with Hepatitis C are able to clear, or get rid ... or lifelong, infection. Over time, chronic Hepatitis C can cause serious ...

  2. 78 FR 46247 - World Hepatitis Day, 2013

    2013-07-31

    ... Hepatitis Day to bring attention to a disease that afflicts one in twelve people worldwide. Viral hepatitis... American deaths every year. Outcomes can significantly improve with treatment, but because viral hepatitis..., we raise awareness about preventing and treating viral hepatitis, and we renew our commitment to...

  3. 76 FR 46181 - World Hepatitis Day, 2011

    2011-08-01

    ... Proclamation Across our Nation, millions of Americans are living with viral hepatitis. As many as three-fourths... save lives and prevent the spread of viral hepatitis. Viral hepatitis is inflammation of the liver, and.... While we have come far, work still needs to be done to prevent and treat this disease. Viral hepatitis...

  4. In situ Raman study of redox state changes of mitochondrial cytochromes in a perfused rat heart

    Brazhe, Nadezda; Treiman, Marek; Faricelli, Barbara

    2013-01-01

    We developed a Raman spectroscopy-based approach for simultaneous study of redox changes in c-and b-type cytochromes and for a semiquantitative estimation of the amount of oxygenated myoglobin in a perfused rat heart. Excitation at 532 nm was used to obtain Raman scattering of the myocardial...... surface of the isolated heart at normal and hypoxic conditions. Raman spectra of the heart under normal pO2 demonstrate unique peaks attributable to reduced c-and b-type cytochromes and oxymyoglobin (oMb). The cytochrome peaks decreased in intensity upon FCCP treatment, as predicted from uncoupling...

  5. Removal of Bound Triton X-100 from Purified Bovine Heart Cytochrome bc1

    Varhač, Rastislav; Robinson, Neal C.; Musatov, Andrej

    2009-01-01

    Cytochrome bc1 isolated from Triton X-100 solubilized mitochondrial membranes contains up to 120 nmol of Triton X-100 bound per nmol of the enzyme. Purified cytochrome bc1 is fully active; however, protein bound Triton X-100 significantly interferes with structural studies of the enzyme. Removal of Triton X-100 bound to bovine cytochrome bc1 was accomplished by incubation with Bio-Beads SM-2 in presence of sodium cholate. Sodium cholate is critical since it does not interfere with the adsorpt...

  6. The Cytochrome bd Oxidase of Porphyromonas gingivalis Contributes to Oxidative Stress Resistance and Dioxygen Tolerance.

    Julia Leclerc

    Full Text Available Porphyromonas gingivalis is an etiologic agent of periodontal disease in humans. The disease is associated with the formation of a mixed oral biofilm which is exposed to oxygen and environmental stress, such as oxidative stress. To investigate possible roles for cytochrome bd oxidase in the growth and persistence of this anaerobic bacterium inside the oral biofilm, mutant strains deficient in cytochrome bd oxidase activity were characterized. This study demonstrated that the cytochrome bd oxidase of Porphyromonas gingivalis, encoded by cydAB, was able to catalyse O2 consumption and was involved in peroxide and superoxide resistance, and dioxygen tolerance.

  7. Magnetic circular dichroism studies on microsomal aryl hydrocarbon hydroxylase: comparison with cytochrome b/sub 5/ and cytochrome P-450/sub cam/

    Vickery, L; Salmon, A; Sauer, K

    1975-01-01

    Magnetic circular dichroism spectra are reported for the visible and near ultraviolet spectral regions of liver microsomes from dimethylbenzanthracene-treated rats. The sequential addition of NADH, dithionite, and carbon monoxide enables us to determine contributions to the magnetic circular dichroism by cytochromes b/sub 5/ and P-450, which dominate the spectra. The magnetic circular dichroism of the microsomal preparation is compared with that of purified oxidized and reduced cytochrome b/sub 5/ from pig liver and with the camphor-complexed and camphor-free oxidized, reduced, and reduced carbonmonoxy cytochrome P-450/sub cam/ from Pseudomonas putida. The magnetic circular dichroism spectra of the membrane bound cytochrome b/sub 5/ are similar to those of the purified protein, indicating that little or no alteration in the environment of the heme occurs during the isolation procedure. The soluble bacterial cytochrome P-450/sub cam/ also appears to be a suitable model for microsomal P-450, although differences in the magnetic circular dichroism intensity are observed for the two enzymes. No effect of dimethylbenzanthracene on the magnetic circular dichroism spectra of induced compared to control rat microsomes could be observed.

  8. Liver scintigraphy of fulminant hepatitis

    Tamaki, Nagara; Ishihara, Takashi; Mori, Toru

    1980-01-01

    The liver scintigraphies of five patients with fulminant hepatitis were examined. Scintiphotos using sup(99m)Tc-phytate were taken within two weeks after the onset. Scintiphotos of 12 normal subjects, 11 cases with acute hepatitis, 17 cases with liver cirrhosis were served as control. Their scintiphotos showed reduction of the size, well-maintained uptake, mostly homogenous RI distribution, and no left lobe enlargement, which could differentiate them from the chronic liver dysfunction. In one of the cases chronological changes in liver scintigraphy were observed. The size of the liver was reduced progressively until the 16th day and re-enlarged at the 30th day and thereafter. Three indices [S/W, (R + L)/W, and L/R] were calculated. S: area of liver, R or L: longitudinal length of the right or left lobe, W: body width. Relative size of the liver expressed by S/W or (R + L)/W showed significant reduction in fulminant hepatitis compared with acute hepatitis. However, they were not different significantly from those of normal subjects. Except for liver cirrhosis, L/R (left lobe swelling index) did not show significant differences among fulminant hepatitis, normal subjects, and acute hepatitis. These indices were also useful in follow-up study of the liver scintigraphy. The liver scintigraphy in the early phase of fulminant hepatitis seems to reflect the degree of massive hepatic necrosis. It is also useful to differentiate chronic hepatic failure. Apparant reduction in scintigraphical liver size seems to suggest poor prognosis, however, it should also kept in mind that the size of the liver in this condition might change quite rapidly and greatly. (author)

  9. Opposing regulation of cytochrome P450 expression by CAR and PXR in hypothyroid mice

    Park, Young Joo [Department of Internal Medicine, Seoul National University College of Medicine (Korea, Republic of); Seoul National University Bundang Hospital, Seoul (Korea, Republic of); Lee, Eun Kyung [Department of Internal Medicine, Seoul National University College of Medicine (Korea, Republic of); Lee, Yoon Kwang [Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030 (United States); Park, Do Joon; Jang, Hak Chul [Department of Internal Medicine, Seoul National University College of Medicine (Korea, Republic of); Moore, David D., E-mail: moore@bcm.edu [Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030 (United States)

    2012-09-01

    Clinical hypothyroidism affects various metabolic processes including drug metabolism. CYP2B and CYP3A are important cytochrome P450 drug metabolizing enzymes that are regulated by the xenobiotic receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2). We evaluated the regulation of the hepatic expression of CYPs by CAR and PXR in the hypothyroid state induced by a low-iodine diet containing 0.15% propylthiouracil. Expression of Cyp3a11 was suppressed in hypothyroid C57BL/6 wild type (WT) mice and a further decrement was observed in hypothyroid CAR{sup −/−} mice, but not in hypothyroid PXR{sup −/−} mice. In contrast, expression of Cyp2b10 was induced in both WT and PXR{sup −/−} hypothyroid mice, and this induction was abolished in CAR{sup −/−} mice and in and CAR{sup −/−} PXR{sup −/−} double knockouts. CAR mRNA expression was increased by hypothyroidism, while PXR expression remained unchanged. Carbamazepine (CBZ) is a commonly used antiepileptic that is metabolized by CYP3A isoforms. After CBZ treatment of normal chow fed mice, serum CBZ levels were highest in CAR{sup −/−} mice and lowest in WT and PXR{sup −/−} mice. Hypothyroid WT or PXR{sup −/−} mice survived chronic CBZ treatment, but all hypothyroid CAR{sup −/−} and CAR{sup −/−} PXR{sup −/−} mice died, with CAR{sup −/−}PXR{sup −/−} mice surviving longer than CAR{sup −/−} mice (12.3 ± 3.3 days vs. 6.3 ± 2.1 days, p = 0.04). All these findings suggest that hypothyroid status affects xenobiotic metabolism, with opposing responses of CAR and PXR and their CYP targets that can cancel each other out, decreasing serious metabolic derangement in response to a xenobiotic challenge. -- Highlights: ► Hypothyroid status activates CAR in mice and induces Cyp2b10 expression. ► Hypothyroid status suppresses PXR activity in mice and represses Cyp3a11 expression. ► These responses balance each other out in normal mice.

  10. Opposing regulation of cytochrome P450 expression by CAR and PXR in hypothyroid mice

    Park, Young Joo; Lee, Eun Kyung; Lee, Yoon Kwang; Park, Do Joon; Jang, Hak Chul; Moore, David D.

    2012-01-01

    Clinical hypothyroidism affects various metabolic processes including drug metabolism. CYP2B and CYP3A are important cytochrome P450 drug metabolizing enzymes that are regulated by the xenobiotic receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2). We evaluated the regulation of the hepatic expression of CYPs by CAR and PXR in the hypothyroid state induced by a low-iodine diet containing 0.15% propylthiouracil. Expression of Cyp3a11 was suppressed in hypothyroid C57BL/6 wild type (WT) mice and a further decrement was observed in hypothyroid CAR −/− mice, but not in hypothyroid PXR −/− mice. In contrast, expression of Cyp2b10 was induced in both WT and PXR −/− hypothyroid mice, and this induction was abolished in CAR −/− mice and in and CAR −/− PXR −/− double knockouts. CAR mRNA expression was increased by hypothyroidism, while PXR expression remained unchanged. Carbamazepine (CBZ) is a commonly used antiepileptic that is metabolized by CYP3A isoforms. After CBZ treatment of normal chow fed mice, serum CBZ levels were highest in CAR −/− mice and lowest in WT and PXR −/− mice. Hypothyroid WT or PXR −/− mice survived chronic CBZ treatment, but all hypothyroid CAR −/− and CAR −/− PXR −/− mice died, with CAR −/− PXR −/− mice surviving longer than CAR −/− mice (12.3 ± 3.3 days vs. 6.3 ± 2.1 days, p = 0.04). All these findings suggest that hypothyroid status affects xenobiotic metabolism, with opposing responses of CAR and PXR and their CYP targets that can cancel each other out, decreasing serious metabolic derangement in response to a xenobiotic challenge. -- Highlights: ► Hypothyroid status activates CAR in mice and induces Cyp2b10 expression. ► Hypothyroid status suppresses PXR activity in mice and represses Cyp3a11 expression. ► These responses balance each other out in normal mice. ► Hypothyroidism sensitizes CAR null mice to toxic effects of carbamazepine.

  11. Asthenia in Children with Chronic Viral Hepatitis

    I.S. Lembryk

    2015-02-01

    Full Text Available In the article results of own researches concerning peculiarities of the course of asthenic syndrome in school-aged children with chronic hepatitis B, C and mixed forms are provided. It is established that chronic hepatitis C as well as a mixed hepatitis are accompanied by more evident symptoms of deadaptation and somatogenic asthenia than hepatitis B in which psychogenic manifestations prevailed. The degree of endogenous intoxication was also higher at hepatitis C.

  12. Failure to incriminate hepatitis B, hepatitis C, and hepatitis E viruses in the aetiology of fulminant non-A non-B hepatitis.

    Mutimer, D; Shaw, J; Neuberger, J; Skidmore, S; Martin, B; Hubscher, S; McMaster, P; Elias, E

    1995-01-01

    Sporadic non-A, non-B hepatitis is the most common indication for liver transplantation in patients presenting with fulminant and subacute liver failure. This study used serological, histological, and molecular biological techniques to examine specimens from 23 consecutive patients transplanted for sporadic non-A, non-B hepatitis. No evidence was found of hepatitis C virus, hepatitis E virus, or 'cryptic' hepatitis B virus infection.

  13. Cytochrome P4501A induction in brown trout exposed to small streams of an urbanised area: results of a five-year-study

    Behrens, Anja; Segner, Helmut

    2005-01-01

    This case study examines the ability of the cytochrome P4501A (CYP1A) biomarker to distinguish the pollution status of two small streams, Kraehenbach and Koersch, receiving different levels of urban and agricultural impact, with low to moderate contamination by arylhydrocarbon receptor (AhR)-binding PAHs and PCBs. Brown trout, Salmo trutta, exposed in enclosure restrictions, showed significant between-stream differences of hepatic CYP1A levels. EROD activities were the better discriminator than CYP1A protein levels. The CYP1A response was consistent and repeatable over the 5-year observation period from 1995 to 1999. In contrast to brown trout, hepatic CYP1A of stone loach, Barbatula barbatula, did not clearly distinguish the streams. The findings of this long-term study lend support to the use of CYP1A as a biomarker of degraded environmental conditions, provided that sufficiently long observation periods are used to average out confounding factors, that sufficiently sensitive detection methods are used, and that a responsive monitoring species is chosen. - The CYP1A biomarker in brown trout robustly ranks the chemical stress status of small streams

  14. Cytochrome P4501A induction in brown trout exposed to small streams of an urbanised area: results of a five-year-study

    Behrens, Anja [Department of Chemical Ecotoxicology, UFZ Centre for Environmental Research, Permoserstr. 15, D-04318 Leipzig (Germany); Segner, Helmut [Department of Chemical Ecotoxicology, UFZ Centre for Environmental Research, Permoserstr. 15, D-04318 Leipzig (Germany)]. E-mail: helmut.segner@itpa.unibe.ch

    2005-07-15

    This case study examines the ability of the cytochrome P4501A (CYP1A) biomarker to distinguish the pollution status of two small streams, Kraehenbach and Koersch, receiving different levels of urban and agricultural impact, with low to moderate contamination by arylhydrocarbon receptor (AhR)-binding PAHs and PCBs. Brown trout, Salmo trutta, exposed in enclosure restrictions, showed significant between-stream differences of hepatic CYP1A levels. EROD activities were the better discriminator than CYP1A protein levels. The CYP1A response was consistent and repeatable over the 5-year observation period from 1995 to 1999. In contrast to brown trout, hepatic CYP1A of stone loach, Barbatula barbatula, did not clearly distinguish the streams. The findings of this long-term study lend support to the use of CYP1A as a biomarker of degraded environmental conditions, provided that sufficiently long observation periods are used to average out confounding factors, that sufficiently sensitive detection methods are used, and that a responsive monitoring species is chosen. - The CYP1A biomarker in brown trout robustly ranks the chemical stress status of small streams.

  15. Modulation of hepatic stellate cells and reversibility of hepatic fibrosis

    Huang, Yu, E-mail: 1293363632@QQ.com [Faculty of Graduate Studies of Guangxi University of Chinese Medicine, Nanning 530001, Guangxi Zhuang Autonomous Region (China); Deng, Xin, E-mail: Hendly@163.com [Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, 10 East China Road, Nanning 530011, Guangxi Zhuang Autonomous Region (China); Liang, Jian, E-mail: lj99669@163.com [Guangxi University of Chinese Medicine, Nanning 530001, Guangxi Zhuang Autonomous Region (China)

    2017-03-15

    Hepatic fibrosis (HF) is the pathological component of a variety of chronic liver diseases. Hepatic stellate cells (HSC) are the main collagen-producing cells in the liver and their activation promotes HF. If HSC activation and proliferation can be inhibited, HF occurrence and development can theoretically be reduced and even reversed. Over the past ten years, a number of studies have addressed this process, and here we present a review of HSC modulation and HF reversal. - Highlights: • We present a review of the modulation of hepatic stellate cells (HSC) and reversibility of hepatic fibrosis (HF). • HSC are the foci of HF occurrence and development, HF could be prevented and treated by modulating HSC. • If HSC activation and proliferation can be inhibited, HF could theoretically be inhibited and even reversed. • Prevention or reversal of HSC activation, or promotion of HSC apoptosis, immune elimination, and senescence may prevent, inhibit or reverse HF.

  16. Liver/kidney microsomal antibody type 1 and liver cytosol antibody type 1 concentrations in type 2 autoimmune hepatitis

    Muratori, L; Cataleta, M; Muratori, P; Lenzi, M; Bianchi, F

    1998-01-01

    Background—Liver/kidney microsomal antibody type 1 (LKM1) and liver cytosol antibody type 1 (LC1) are the serological markers of type 2 autoimmune hepatitis (AIH). 
Aims—Since LKM1 and LC1 react against two distinct liver specific autoantigens (cytochrome P450IID6 (CYP2D6) and a 58 kDa cytosolic polypeptide respectively), the aim was to see whether LKM1 and LC1 concentrations correlate with liver disease activity. 
Patients—Twenty one patients with type 2 AIH were studied. 
Methods—A...

  17. Hepatic biotransformation of alkylresorcinols is mediated via cytochrome P450 and beta-oxidation: a proof of concept study

    Alkylresorcinols (AR) are phenolic lipids present in the bran of some cereals. AR may serve as a biomarker for whole grain wheat and rye intake. While AR pharmacokinetics and two major metabolites have been reported, the metabolic pathways contributing to their relatively rapid elimination from the ...

  18. Dengue fever with hepatitis E and hepatitis A infection.

    Yakoob, Javed; Jafri, Wasim; Siddiqui, Shaheer; Riaz, Mehmood

    2009-03-01

    Infection with dengue viruses produces a spectrum of clinical illness ranging from a nonspecific viral syndrome to severe and fatal haemorrhagic disease. Important risk factors include the strain and serotype of the infecting virus, as well as the age, immune status, and genetic predisposition of the patient. The teaching point in this case study was Dengue fever which occurred concomitantly with Hepatitis A and Hepatitis E virus infection.

  19. Hepatic glucose utilization in hepatic steatosis and obesity

    Keramida, Georgia; Hunter, James; Peters, Adrien?Michael

    2016-01-01

    Hepatic steatosis is associated with obesity and insulin resistance. Whether hepatic glucose utilization rate (glucose phosphorylation rate; MRglu) is increased in steatosis and/or obesity is uncertain. Our aim was to determine the separate relationships of steatosis and obesity with MRglu. Sixty patients referred for routine PET/CT had dynamic PET imaging over the abdomen for 30?min post-injection of F-18-fluorodeoxyglucose (FDG), followed by Patlak?Rutland graphical analysis of the liver us...

  20. Autoimmune hepatitis in children.

    Mieli-Vergani, Giorgina; Vergani, Diego

    2002-08-01

    AIH, ASC, and de novo AIH after liver transplantation are childhood liver diseases of an autoimmune nature. The mode of presentation of AIH in childhood is variable, and the disease should be suspected and excluded in all children presenting with symptoms and signs of prolonged or severe acute liver disease. Although corticosteroids are effective in all types of childhood AIH, patients with LKM1 have a higher frequency of acute hepatic failure and relapse after corticosteroid withdrawal than do patients with ANA/SMA. ASC occurs commonly in the absence of inflammatory bowel disease, requires cholangiography for diagnosis, and improves during corticosteroid therapy. The development of AIH de novo in children who undergo liver transplantation for nonautoimmune liver disease may reflect interference with the maturation of T cells by immunosuppressive drugs.

  1. Sulfite oxidase activity of cytochrome c: Role of hydrogen peroxide

    Murugesan Velayutham

    2016-03-01

    Full Text Available In humans, sulfite is generated endogenously by the metabolism of sulfur containing amino acids such as methionine and cysteine. Sulfite is also formed from exposure to sulfur dioxide, one of the major environmental pollutants. Sulfite is used as an antioxidant and preservative in dried fruits, vegetables, and beverages such as wine. Sulfite is also used as a stabilizer in many drugs. Sulfite toxicity has been associated with allergic reactions characterized by sulfite sensitivity, asthma, and anaphylactic shock. Sulfite is also toxic to neurons and cardiovascular cells. Recent studies suggest that the cytotoxicity of sulfite is mediated by free radicals; however, molecular mechanisms involved in sulfite toxicity are not fully understood. Cytochrome c (cyt c is known to participate in mitochondrial respiration and has antioxidant and peroxidase activities. Studies were performed to understand the related mechanism of oxidation of sulfite and radical generation by ferric cytochrome c (Fe3+cyt c in the absence and presence of H2O2. Electron paramagnetic resonance (EPR spin trapping studies using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO were performed with sulfite, Fe3+cyt c, and H2O2. An EPR spectrum corresponding to the sulfite radical adducts of DMPO (DMPO-SO3- was obtained. The amount of DMPO-SO3- formed from the oxidation of sulfite by the Fe3+cyt c increased with sulfite concentration. In addition, the amount of DMPO-SO3- formed by the peroxidase activity of Fe3+cyt c also increased with sulfite and H2O2 concentration. From these results, we propose a mechanism in which the Fe3+cyt c and its peroxidase activity oxidizes sulfite to sulfite radical. Our results suggest that Fe3+cyt c could have a novel role in the deleterious effects of sulfite in biological systems due to increased production of sulfite radical. It also shows that the increased production of sulfite radical may be responsible for neurotoxicity and some of the injuries which

  2. Toxicologic study of carboxyatractyloside (active principle in cocklebur--Xanthium strumarium) in rats treated with enzyme inducers and inhibitors and glutathione precursor and depletor.

    Hatch, R C; Jain, A V; Weiss, R; Clark, J D

    1982-01-01

    Male rats (10 rats/group) were treated with phenobarbital (PB), phenylbutazone (PBZ), stanozolol (3 inducers of cytochrome P450-dependent enzymes), piperonyl butoxide (PBO; a P450 inhibitor), cobaltous chloride (CoCl2; an inhibitor of hemoprotein synthesis), 5,6-benzoflavone (BNF; an inducer of cytochrome P448 dependent enzymes), cysteine [CYS; a glutathione (GSH) precursor], or ethyl maleate (EM; a GSH depletor). The rats were then given a calculated LD50 dosage (13.5 mg/kg of body weight) of carboxyatractyloside (CAT) intraperitoneally. Clinical signs of toxicosis, duration of illness, lethality, gross lesions, and hepatic and renal histopathologic lesions were recorded. Seemingly, (i) CAT toxicosis has independent lethal and cytotoxic components (PBZ decreased lethality and cytotoxicity; CoCl2 decreased cytotoxicity but not lethality; BNF decreased duration of illness, and perhaps lethality, but not cytotoxicity); (ii) CAT cytotoxicity could be partly due to an active metabolite formed by de novo-synthesized, P450-/P448-independent hemoprotein (PBZ and CoCl2 had anticytotoxic effects, but PB, stanozolol, PBO, and BNF did not); (iii) CAT detoxification may occur partly through a hemoprotein-independent, PBZ-inducible enzyme, and partly through a P448-dependent (BNF-inducible) enzyme; and (iv) CAT detoxification apparently is not P450 or GSH-dependent because PB, stanozolol, and CYS had no beneficial effects, and PBO, CoCl2, and EM did not enhance toxicosis. Metabolism of CAT may have a role in its cytotoxic and lethal effects.

  3. Polycyclic aromatic hydrocarbon metabolism in mullets, Chelon labrosus, treated by polychlorinated biphenyls

    Narbonne, J.F.; Suteau, P.; Daubeze, M.; Audy, C.

    1987-01-01

    Contamination of the ocean by hydrocarbons has become a major environmental problem. Consequently, it is not surprising that residues of potentially toxic xenobiotics, such as benzo(a)pyrene (B(a)P), are present in marine species used as human food. The oxidative metabolism of aromatic hydrocarbons proceeds via intermediate arene oxides. Some of these metabolites are very reactive electrophiles and may interact with cellular macromolecules such as proteins, DNA and RNA. Thus, the ability of an organism to further metabolize arene oxides can be an important protective mechanism against the possible toxic effect of these molecules. The existence of hepatic cytochrome P-450 dependent monooxygenase activities in fish is now well established. The exposure of fish to polychlorinated biphenyls (PCB) increases both the monooxygenase activities and the total amount of cytochrome P-450 in the microsomal fractions of fish liver. The purpose of this study was to compare the toxication-detoxication balance in both control and PCB induced estuarine fish (Grey mullets)

  4. Influence of nutrition on liver oxidative metabolism.

    Jorquera, F; Culebras, J M; González-Gallego, J

    1996-06-01

    The liver plays a major role in the disposition of the majority of drugs. This is due to the presence of several drug-metabolizing enzyme systems, including a group of membrane-bound mixed-function oxidative enzymes, mainly the cytochrome P450 system. Hepatic oxidative capacity can be assessed by changes in antipyrine metabolism. Different drugs and other factors may induce or inhibit the cytochrome P450-dependent system. This effect is important in terms of the efficacy or toxicity of drugs that are substrates for the system. Microsomal oxidation in animals fed with protein-deficient diets is depressed. The mixed-function oxidase activity recovers after a hyperproteic diet or the addition of lipids. Similar findings have been reported in patients with protein-calorie malnutrition, although results in the elderly are conflicting. Different studies have revealed that microsomal oxidation is impaired by total parenteral nutrition and that this effect is absent when changing the caloric source from carbohydrates to a conventional amino acid solution or after lipid addition, especially when administered as medium-chain/long-chain triglyceride mixtures. Peripheral parenteral nutrition appears to increase antipyrine clearance.

  5. The epidemiology of viral hepatitis in Qatar

    Bener Abdulbari

    2009-01-01

    Full Text Available Viral hepatitis is a major public health problem in many countries all over the world and especially in Middle East, Asia, East-Europe, and Africa. The aim of our study was to assess the incidence of viral hepatitis A, B and C in Qatar and compare it with other countries. This is a retrospective cohort study, which was conducted at Hamad General Hospital, State of Qatar from 2002-2006. Patients who were screened and diagnosed with viral hepatitis were included in this study. The diagnostic classification of definite viral hepatitis was made in accordance with criteria based on the International Classification of Disease tenth revision (ICD-10. A total of 527 cases of hepatitis C, 396 cases of hepatitis B, 162 cases of hepatitis A and 108 cases of unspecified were reported during the year 2006. Reported incidence rate per 10,000 populations during the year 2006 for hepatitis A was 1.9, hepatitis B 4.7, and Hepatitis C 6.3. The proportion of hepatitis B and C was significantly higher in male population than females across the years (2002-2006. Hepatitis A was more prevalent in children below 15 years (72.3%, hepatitis B in adults aged above 15 years, and hepatitis C in the population above 35 years of age. The incidence of hepatitis A has been declining in Qataris and increasing in expatriates. There was a significant relationship in gender and age group of the patients with hepatitis A, B and C. We conclude that hepatitis has become a national health issue in Qatar. The incidence rate of hepatitis in Qatar is comparable to its neighboring countries, United Arab Emirates and Saudi Arabia. There is a need for further research on hepatitis and the associated risk factors.

  6. Conjugation of cytochrome c with hydrogen titanate nanotubes: novel conformational state with implications for apoptosis

    Ray, Moumita; Mazumdar, Shyamalava [Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Mumbai 400005 (India); Chatterjee, Sriparna; Das, Tanmay; Bhattacharyya, Somnath; Ayyub, Pushan, E-mail: somnath@tifr.res.in, E-mail: pushan@tifr.res.in, E-mail: shyamal@tifr.res.in [Department of Condensed Matter Physics and Materials Science, Tata Institute of Fundamental Research, Homi Bhabha Road, Mumbai 400005 (India)

    2011-10-14

    We show that hydrogen titanate (H{sub 2}Ti{sub 3}O{sub 7}) nanotubes form strongly associated reversible nano-bio-conjugates with the vital respiratory protein, cytochrome c. Resonance Raman spectroscopy along with direct electrochemical studies indicate that in this nano-bio-conjugate, cytochrome c exists in an equilibrium of two conformational states with distinctly different formal redox potentials and coordination geometries of the heme center. The nanotube-conjugated cytochrome c also showed enhanced peroxidase activity similar to the membrane-bound protein that is believed to be an apoptosis initiator. This suggests that such a nanotube-cytochrome c conjugate may be a good candidate for cancer therapy applications.

  7. Prognostic Value of Cytochrome C and Cytokines in Acute Viral Encephalopathy

    J Gordon Millichap

    2006-06-01

    Full Text Available Serum cytochrome c and cytokines were evaluated as prognostic predictors in 29 children (ages 9 mos to 9 yrs 11 mos with viral acute encephalopathies and multiple organ failure at Fukushima Medical University School of Medicine, Japan.

  8. Evidence that Na+-pumping occurs through the D-channel in Vitreoscilla cytochrome bo

    Kim, Seong K.; Stark, Benjamin C.; Webster, Dale A.

    2005-01-01

    The operon (cyo) encoding the Na + -pumping respiratory terminal oxidase (cytochrome bo) of the bacterium Vitreoscilla was transformed into Escherichia coli GV100, a deletion mutant of cytochrome bo. This was done for the wild type operon and five mutants in three conserved Cyo subunit I amino acids known to be crucial for H + transport in the E. coli enzyme, one near the nuclear center, one in the K-channel, and one in the D-channel. CO-binding, NADH and ubiquinol oxidase, and Na + -pumping activities were all substantially inhibited by each mutation. The wild type Vitreoscilla cytochrome bo can pump Na + against a concentration gradient, resulting in a transmembrane concentration differential of 2-3 orders of magnitude. It is proposed that Vitreoscilla cytochrome bo pumps four Na + through the D-channel to the exterior and transports four H + through the K-channel for the reduction of each O 2

  9. A mitochondrial cytochrome b mutation causing severe respiratory chain enzyme deficiency in humans and yeast.

    Blakely, E.L.; Mitchell, A.L.; Fisher, N.; Meunier, B.; Nijtmans, L.G.J.; Schaefer, A.M.; Jackson, M.J.; Turnbull, D.M.; Taylor, R.W.

    2005-01-01

    Whereas the majority of disease-related mitochondrial DNA mutations exhibit significant biochemical and clinical heterogeneity, mutations within the mitochondrially encoded human cytochrome b gene (MTCYB) are almost exclusively associated with isolated complex III deficiency in muscle and a clinical

  10. Hepatitis E and Maternal Deaths

    Dr. Alain Labrique, assistant professor in the Department of International Health and Department of Epidemiology at the Bloomberg School of Public Health, gives us his perspective on hepatitis E and maternal deaths.

  11. Viral hepatitis vaccination during pregnancy.

    Zhao, Yueyuan; Jin, Hui; Zhang, Xuefeng; Wang, Bei; Liu, Pei

    2016-04-02

    Viral hepatitis is a serious global public health problem. It is also a common cause of jaundice and gestational complications in pregnant women. Moreover, infected mothers can transmit the virus to their fetus or neonate, which may increase disease burden and decrease quality of life. To date, commercial vaccines have been developed for hepatitis A, B, and E and are available to the general population. The Advisory Committee on Immunization Practices currently accepts emergency vaccination against hepatitis A and B during pregnancy due to benefits that overweight the potential risks. While there are limited data from trials with limited numbers of samples that suggest the efficacy or safety of hepatitis B and E vaccines in pregnant women, additional data are necessary to provide evidence of vaccination during pregnancy.

  12. Dopamine agents for hepatic encephalopathy

    Junker, Anders Ellekær; Als-Nielsen, Bodil; Gluud, Christian

    2014-01-01

    BACKGROUND: Patients with hepatic encephalopathy may present with extrapyramidal symptoms and changes in basal ganglia. These changes are similar to those seen in patients with Parkinson's disease. Dopamine agents (such as bromocriptine and levodopa, used for patients with Parkinson's disease) have...... therefore been assessed as a potential treatment for patients with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of dopamine agents versus placebo or no intervention for patients with hepatic encephalopathy. SEARCH METHODS: Trials were identified through the Cochrane...... hepatic encephalopathy that were published during 1979 to 1982 were included. Three trials assessed levodopa, and two trials assessed bromocriptine. The mean daily dose was 4 grams for levodopa and 15 grams for bromocriptine. The median duration of treatment was 14 days (range seven to 56 days). None...

  13. Importance of c-Type cytochromes for U(VI reduction by Geobacter sulfurreducens

    Leang Ching

    2007-03-01

    Full Text Available Abstract Background In order to study the mechanism of U(VI reduction, the effect of deleting c-type cytochrome genes on the capacity of Geobacter sulfurreducens to reduce U(VI with acetate serving as the electron donor was investigated. Results The ability of several c-type cytochrome deficient mutants to reduce U(VI was lower than that of the wild type strain. Elimination of two confirmed outer membrane cytochromes and two putative outer membrane cytochromes significantly decreased (ca. 50–60% the ability of G. sulfurreducens to reduce U(VI. Involvement in U(VI reduction did not appear to be a general property of outer membrane cytochromes, as elimination of two other confirmed outer membrane cytochromes, OmcB and OmcC, had very little impact on U(VI reduction. Among the periplasmic cytochromes, only MacA, proposed to transfer electrons from the inner membrane to the periplasm, appeared to play a significant role in U(VI reduction. A subpopulation of both wild type and U(VI reduction-impaired cells, 24–30%, accumulated amorphous uranium in the periplasm. Comparison of uranium-accumulating cells demonstrated a similar amount of periplasmic uranium accumulation in U(VI reduction-impaired and wild type G. sulfurreducens. Assessment of the ability of the various suspensions to reduce Fe(III revealed no correlation between the impact of cytochrome deletion on U(VI reduction and reduction of Fe(III hydroxide and chelated Fe(III. Conclusion This study indicates that c-type cytochromes are involved in U(VI reduction by Geobacter sulfurreducens. The data provide new evidence for extracellular uranium reduction by G. sulfurreducens but do not rule out the possibility of periplasmic uranium reduction. Occurrence of U(VI reduction at the cell surface is supported by the significant impact of elimination of outer membrane cytochromes on U(VI reduction and the lack of correlation between periplasmic uranium accumulation and the capacity for uranium

  14. P450 reductase and cytochrome b5 interactions with cytochrome P450: Effects on house fly CYP6A1 catalysis

    Murataliev, Marat B.; Guzov, Victor M.; Walker, F. Ann; Feyereisen, René

    2008-01-01

    The interactions of protein components of the xenobiotic-metabolizing cytochrome P450 system, CYP6A1, P450 reductase, and cytochrome b5 from the house fly (Musca domestica) have been characterized. CYP6A1 activity is determined by the concentration of the CYP6A1-P450 reductase complex, regardless of which protein is present in excess. Both holo- and apo-b5 stimulated CYP6A1 heptachlor epoxidase and steroid hydroxylase activities and influenced the regioselectivity of testosterone hydroxylatio...

  15. APLASTIC ANEMIA AND VIRAL HEPATITIS

    Laura Cudillo

    2009-11-01

    Liver histology is characterized by T cell infiltrating the parenchyma as reported in acute hepatitis. Recently in HAA it has been demonstrated intrahepatic  and blood lymphocytes with  T cell repertoire similar to that of confirmed viral acute hepatitis. The expanded T cell clones return to a normal distribution after response to immunosuppressive treatment, suggesting the antigen or T cell clearance. Therapeutic options are the same as acquired aplastic anemia.

  16. [Immunomodulators with an 8-azasteroid structure as inducers of liver cytochrome P-450].

    Kuz'mitskiĭ, B B; Dad'kov, I G; Mashkovich, A E; Stoma, O V; Slepneva, L M

    1990-01-01

    Two structural analogues of D-homo-8-azasteroids, both an immunostimulant and an immunodepressant, are inductors of the liver cytochrome P-450 in animals. This capability was shown by means of both a decrease of the hexenal sleep duration in the pharmacological test and an increase of the quantity of cytochrome P-450 and the rate of N-demethylation of aminopyrine in the biochemical assays.

  17. Evolution of NADPH-cytochrome P450 oxidoreductases (POR) in Apiales - POR 1 is missing

    Andersen, Trine Bundgaard; Hansen, Niels Bjørn; Laursen, Tomas

    2016-01-01

    The NADPH-dependent cytochrome P450 oxidoreductase (POR) is the obligate electron donor to eukaryotic microsomal cytochromes P450 enzymes. The number of PORs within plant species is limited to one to four isoforms, with the most common being two PORs per plant. These enzymes provide electrons to ...... (available from the SRA at NCBI). All three genes were shown to be functional upon reconstitution into nanodiscs, confirming that none of the isoforms are pseudogenes....

  18. Utilizing Chemical Genomics to Identify Cytochrome b as a Novel Drug Target for Chagas Disease.

    Shilpi Khare

    2015-07-01

    Full Text Available Unbiased phenotypic screens enable identification of small molecules that inhibit pathogen growth by unanticipated mechanisms. These small molecules can be used as starting points for drug discovery programs that target such mechanisms. A major challenge of the approach is the identification of the cellular targets. Here we report GNF7686, a small molecule inhibitor of Trypanosoma cruzi, the causative agent of Chagas disease, and identification of cytochrome b as its target. Following discovery of GNF7686 in a parasite growth inhibition high throughput screen, we were able to evolve a GNF7686-resistant culture of T. cruzi epimastigotes. Clones from this culture bore a mutation coding for a substitution of leucine by phenylalanine at amino acid position 197 in cytochrome b. Cytochrome b is a component of complex III (cytochrome bc1 in the mitochondrial electron transport chain and catalyzes the transfer of electrons from ubiquinol to cytochrome c by a mechanism that utilizes two distinct catalytic sites, QN and QP. The L197F mutation is located in the QN site and confers resistance to GNF7686 in both parasite cell growth and biochemical cytochrome b assays. Additionally, the mutant cytochrome b confers resistance to antimycin A, another QN site inhibitor, but not to strobilurin or myxothiazol, which target the QP site. GNF7686 represents a promising starting point for Chagas disease drug discovery as it potently inhibits growth of intracellular T. cruzi amastigotes with a half maximal effective concentration (EC50 of 0.15 µM, and is highly specific for T. cruzi cytochrome b. No effect on the mammalian respiratory chain or mammalian cell proliferation was observed with up to 25 µM of GNF7686. Our approach, which combines T. cruzi chemical genetics with biochemical target validation, can be broadly applied to the discovery of additional novel drug targets and drug leads for Chagas disease.

  19. Glaucoma and Cytochrome P4501B1 Gene Mutations

    Mukesh Tanwar

    2010-01-01

    Full Text Available Developmental anomalies of the ocular anterior chamber angle may lead to an incomplete development of the structures that form the conventional aqueous outflow pathway. Thus, disorders that present with such dysfunction tend to be associated with glaucoma. Among them, Axenfeld-Rieger (ARS malformation is a rare clinical entity with an estimated prevalence of one in every 200,000 individuals. The changes in eye morphogenesis in ARS are highly penetrant and are associated with 50% risk of development of glaucoma. Mutations in the cytochrome P4501B1 (CYP1B1 gene have been reported to be associated with primary congenital glaucoma and other forms of glaucoma and mutations in pituitary homeobox 2 (PITX2 gene have been identified in ARS in various studies. This case was negative for PITX2 mutations and compound heterozygote for CYP1B1 mutations. Clinical manifestations of this patient include bilateral elevated intraocular pressure (>40 mmHg with increased corneal diameter (>14 mm and corneal opacity. Patient also had iridocorneal adhesions, anteriorly displaced Schwalbe line, anterior insertion of iris, broad nasal bridge and protruding umbilicus. This is the first study from north India reporting CYP1B1 mutations in Axenfeld-Rieger syndrome with bilateral buphthalmos and early onset glaucoma. Result of this study supports the role of CYP1B1 as a causative gene in ASD disorders and its role in oculogenesis.

  20. Enhanced mitochondrial degradation of yeast cytochrome c with amphipathic structures.

    Chen, Xi; Moerschell, Richard P; Pearce, David A; Ramanan, Durga D; Sherman, Fred

    2005-02-01

    The dispensable N-terminus of iso-1-cytochrome c (iso-1) in the yeast Saccharomyces cerevisiae was replaced by 11 different amphipathic structures. Rapid degradation of the corresponding iso-1 occurred, with the degree of degradation increasing with the amphipathic moments; and this amphipathic-dependent degradation was designated ADD. ADD occurred with the holo-forms in the mitochondria but not as the apo-forms in the cytosol. The extreme mutant type degraded with a half-life of approximately 12 min, whereas the normal iso-1 was stable over hours. ADD was influenced by the rho+/rho- state and by numerous chromosomal genes. Most importantly, ADD appeared to be specifically suppressed to various extents by deletions of any of the YME1, AFG3, or RCA1 genes encoding membrane-associated mitochondrial proteases, probably because the amphipathic structures caused a stronger association with the mitochondrial inner membrane and its associated proteases. The use of ADD assisted in the differentiation of substrates of different mitochondrial degradation pathways.

  1. Clinical Pharmacogenetics of Cytochrome P450-Associated Drugs in Children

    Ida Aka

    2017-11-01

    Full Text Available Cytochrome P450 (CYP enzymes are commonly involved in drug metabolism, and genetic variation in the genes encoding CYPs are associated with variable drug response. While genotype-guided therapy has been clinically implemented in adults, these associations are less well established for pediatric patients. In order to understand the frequency of pediatric exposures to drugs with known CYP interactions, we compiled all actionable drug–CYP interactions with a high level of evidence using Clinical Pharmacogenomic Implementation Consortium (CPIC data and surveyed 10 years of electronic health records (EHR data for the number of children exposed to CYP-associated drugs. Subsequently, we performed a focused literature review for drugs commonly used in pediatrics, defined as more than 5000 pediatric patients exposed in the decade-long EHR cohort. There were 48 drug–CYP interactions with a high level of evidence in the CPIC database. Of those, only 10 drugs were commonly used in children (ondansetron, oxycodone, codeine, omeprazole, lansoprazole, sertraline, amitriptyline, citalopram, escitalopram, and risperidone. For these drugs, reports of the drug–CYP interaction in cohorts including children were sparse. There are adequate data for implementation of genotype-guided therapy for children for three of the 10 commonly used drugs (codeine, omeprazole and lansoprazole. For the majority of commonly used drugs with known CYP interactions, more data are required to support pharmacogenomic implementation in children.

  2. Becoming a Peroxidase: Cardiolipin-Induced Unfolding of Cytochrome c

    Muenzner, Julia; Toffey, Jason R.; Hong, Yuning; Pletneva, Ekaterina V.

    2014-01-01

    Interactions of cytochrome c (cyt c) with a unique mitochondrial glycerophospholipid cardiolipin (CL) are relevant for the protein’s function in oxidative phosphorylation and apoptosis. Binding to CL-containing membranes promotes cyt c unfolding and dramatically enhances the protein’s peroxidase activity, which is critical in early stages of apoptosis. We have employed a collection of seven dansyl variants of horse heart cyt c to probe the sequence of steps in this functional transformation. Kinetic measurements have unraveled four distinct processes during CL-induced cyt c unfolding: rapid protein binding to CL liposomes; rearrangements of protein substructures with small unfolding energies; partial insertion of the protein into the lipid bilayer; and extensive protein restructuring leading to “open” extended structures. While early rearrangements depend on a hierarchy of foldons in the native structure, the later process of large-scale unfolding is influenced by protein interactions with the membrane surface. The opening of the cyt c structure exposes the heme group, which enhances the protein’s peroxidase activity and also frees the C-terminal helix to aid in the translocation of the protein through CL membranes. PMID:23713573

  3. Force modulation and electrochemical gating of conductance in a cytochrome

    Davis, Jason J.; Peters, Ben; Xi, Wang

    2008-09-01

    Scanning probe methods have been used to measure the effect of electrochemical potential and applied force on the tunnelling conductance of the redox metalloprotein yeast iso-1-cytochrome c (YCC) at a molecular level. The interaction of a proximal probe with any sample under test will, at this scale, be inherently perturbative. This is demonstrated with conductive probe atomic force microscopy (CP-AFM) current-voltage spectroscopy in which YCC, chemically adsorbed onto pristine Au(111) via its surface cysteine residue, is observed to become increasingly compressed as applied load is increased, with concomitant decrease in junction resistance. Electrical contact at minimal perturbation, where probe-molecule coupling is comparable to that in scanning tunnelling microscopy, brings with it the observation of negative differential resistance, assigned to redox-assisted probe-substrate tunnelling. The role of the redox centre in conductance is also resolved in electrochemical scanning tunnelling microscopy assays where molecular conductance is electrochemically gateable through more than an order of magnitude.

  4. Regulation of the cytochrome P450 2A genes

    Su Ting; Ding Xinxin

    2004-01-01

    Cytochrome P450 monooxygenases of the CYP2A subfamily play important roles in xenobiotic disposition in the liver and in metabolic activation in extrahepatic tissues. Many of the CYP2A transcripts and enzymes are inducible by xenobiotic compounds, and the expression of at least some of the CYP2A genes is influenced by physiological status, such as circadian rhythm, and pathological conditions, such as inflammation, microbial infection, and tumorigenesis. Variability in the expression of the CYP2A genes, which differs by species, animal strain, gender, and organ, may alter the risks of chemical toxicity for numerous compounds that are CYP2A substrates. The mechanistic bases of these variabilities are generally not well understood. However, recent studies have yielded interesting findings in several areas, such as the role of nuclear factor 1 in the tissue-selective expression of CYP2A genes in the olfactory mucosa (OM); the roles of constitutive androstane receptor, pregnane X receptor (PXR), and possibly, peroxisome proliferator-activated receptors in transcriptional regulation of the Cyp2a5 gene; and the involvement of heterogeneous nuclear ribonucleoprotein A1 in pyrazole-induced stabilization of CYP2A5 mRNA. The aims of this minireview are to summarize current knowledge of the regulation of the CYP2A genes in rodents and humans, and to stimulate further mechanistic studies that will ultimately improve our ability to determine, and to understand, these variabilities in humans

  5. Expression of cytochrome P450 regulators in cynomolgus macaque.

    Uno, Yasuhiro; Yamazaki, Hiroshi

    2017-09-11

    1. Cytochrome P450 (P450) regulators including nuclear receptors and transcription factors have not been fully investigated in cynomolgus macaques, an important species used in drug metabolism studies. In this study, we analyzed 17 P450 regulators by sequence and phylogenetic analysis, and tissue expression. 2. Gene and genome structures of 17 P450 regulators were similar to the human orthologs, and the deduced amino acid sequences showed high sequence identities (92-95%) and more closely clustered in a phylogenetic tree, with the human orthologs. 3. Many of the P450 regulator mRNAs were preferentially expressed in the liver, kidney, and/or jejunum. Among the P450 regulator mRNAs, PXR was most abundant in the liver and jejunum, and HNF4α in the kidney. In the liver, the expression of most P450 regulator mRNAs did not show significant differential expression (>2.5-fold) between cynomolgus macaques bred in Cambodia, China, and Indonesia, or rhesus macaques. 4. By correlation analysis, most of the P450 regulators were significantly (p < 0.05) correlated to other P450 regulators, and many of them were also significantly (p < 0.05) correlated with P450s. 5. These results suggest that 17 P450 regulators of cynomolgus macaques had similar molecular characteristics to the human orthologs.

  6. Interaction of rocuronium with human liver cytochromes P450.

    Anzenbacherova, Eva; Spicakova, Alena; Jourova, Lenka; Ulrichova, Jitka; Adamus, Milan; Bachleda, Petr; Anzenbacher, Pavel

    2015-02-01

    Rocuronium is a neuromuscular blocking agent acting as a competitive antagonist of acetylcholine. Results of an inhibition of eight individual liver microsomal cytochromes P450 (CYP) are presented. As the patients are routinely premedicated with diazepam, possible interaction of diazepam with rocuronium has been also studied. Results indicated that rocuronium interacts with human liver microsomal CYPs by binding to the substrate site. Next, concentration dependent inhibition of liver microsomal CYP3A4 down to 42% (at rocuronium concentration 189 μM) was found. This effect has been confirmed with two CYP3A4 substrates, testosterone (formation of 6β-hydroxytestosterone) and diazepam (temazepam formation). CYP2C9 and CYP2C19 activities were inhibited down to 75-80% (at the same rocuronium concentration). Activities of other microsomal CYPs have not been inhibited by rocuronium. To prove the possibility of rocuronium interaction with other drugs (diazepam), the effect of rocuronium on formation of main diazepam metabolites, temazepam (by CYP3A4) and desmethyldiazepam, (also known as nordiazepam; formed by CYP2C19) in primary culture of human hepatocytes has been examined. Rocuronium has caused inhibition of both reactions by 20 and 15%, respectively. The results open a possibility that interactions of rocuronium with drugs metabolized by CYP3A4 (and possibly also CYP2C19) may be observed. Copyright © 2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

  7. Direct observation of vibrational energy flow in cytochrome c.

    Fujii, Naoki; Mizuno, Misao; Mizutani, Yasuhisa

    2011-11-10

    Vibrational energy flow in ferric cytochrome c has been examined by picosecond time-resolved anti-Stokes ultraviolet resonance Raman (UVRR) measurements. By taking advantage of the extremely short nonradiative excited state lifetime of heme in the protein (energy of 20000-25000 cm(-1) was optically deposited selectively at the heme site. Subsequent energy relaxation in the protein moiety was investigated by monitoring the anti-Stokes UVRR intensities of the Trp59 residue, which is a single tryptophan residue involved in the protein that is located close to the heme group. It was found from temporal changes of the anti-Stokes UVRR intensities that the energy flow from the heme to Trp59 and the energy release from Trp59 took place with the time constants of 1-3 and ~8 ps, respectively. These data are consistent with the time constants for the vibrational relaxation of the heme and heating of water reported for hemeproteins. The kinetics of the energy flow were not affected by the amount of excess energy deposited at the heme group. These results demonstrate that the present technique is a powerful tool for studying the vibrational energy flow in proteins.

  8. Polycyclic aromatic hydrocarbons and cytochrome P450 in HIV pathogenesis

    Rao, P. S. S.; Kumar, Santosh

    2015-01-01

    High prevalence of cigarette smoking in HIV patients is associated with increased HIV pathogenesis and disease progression. While the effect of smoking on the occurrence of lung cancer has been studied extensively, the association between smoking and HIV pathogenesis is poorly studied. We have recently shown the possible role of cytochrome P450 (CYP) in smoking/nicotine-mediated viral replication. In this review, we focus on the potential role of CYP pathway in polycyclic aromatic hydrocarbons (PAH), important constituents of cigarette smoke, mediated HIV pathogenesis. More specifically, we will discuss the role of CYP1A1 and CYP1B1, which are the major PAH-activating CYP enzymes. Our results have shown that treatment with cigarette smoke condensate (CSC) increases viral replication in HIV-infected macrophages. CSC contains PAH, which are known to be activated by CYP1A1 and CYP1B1 into procarcinogens/toxic metabolites. The expression of these CYPs is regulated by aryl hydrocarbon receptors (AHR), the cellular target of PAH, and an important player in various diseases including cancer. We propose that PAH/AHR-mediated CYP pathway is a novel target to develop new interventions for HIV positive smokers. PMID:26082767

  9. Cytochromes P450: History, Classes, Catalytic Mechanism, and Industrial Application.

    Cook, D J; Finnigan, J D; Cook, K; Black, G W; Charnock, S J

    Cytochromes P450, a family of heme-containing monooxygenases that catalyze a diverse range of oxidative reactions, are so-called due to their maximum absorbance at 450nm, ie, "Pigment-450nm," when bound to carbon monoxide. They have appeal both academically and commercially due to their high degree of regio- and stereoselectivity, for example, in the area of active pharmaceutical ingredient synthesis. Despite this potential, they often exhibit poor stability, low turnover numbers and typically require electron transport protein(s) for catalysis. P450 systems exist in a variety of functional domain architectures, organized into 10 classes. P450s are also divided into families, each of which is based solely on amino acid sequence homology. Their catalytic mechanism employs a very complex, multistep catalytic cycle involving a range of transient intermediates. Mutagenesis is a powerful tool for the development of improved biocatalysts and has been used extensively with the archetypal Class VIII P450, BM3, from Bacillus megaterium, but with the increasing scale of genomic sequencing, a huge resource is now available for the discovery of novel P450s. © 2016 Elsevier Inc. All rights reserved.

  10. Differences in renal metabolism of insulin and cytochrome c

    Herrman, J.; Simmons, R.E.; Frank, B.H.; Rabkin, R.

    1988-01-01

    Kidneys degrade small proteins such as cytochrome c (CYT c) by the classic lysosomal pathway. However, because alternate routes for the transport and degradation of protein hormones have been identified in other tissues, the authors set out to determine whether extralysosomal sites might participate in the renal degradation of insulin. First, they compared the effect of the lysosomal inhibitor NH 4 Cl on insulin and CYT c degradation by isolated perfused rat kidneys. After kidneys were loaded with radiolabeled proteins to allow for absorption and transport to lysosomes, degradation was measured in the presence or absence of inhibitors. Next they followed the subcellular distribution of 125 I-labeled insulin in kidneys exposed to 125 I-labeled insulin in vivo or when isolated and perfused. Under both circumstances the distribution of insulin on a linear sucrose gradient differed from that of the lysosomal enzyme N-acetyl-β-glucosaminidase. In contrast, [ 14 CH 3 ]CYT c, injected in vivo, distributed over a density similar to the lysosomal marker. Thus important differences exist between the renal metabolism of CYT c, which proceeds in lysosomes, and the renal metabolism of insulin. These include rate of degradation, sensitivity to NH 4 Cl, and subcellular sites of localization. Accordingly, they suggest that insulin degradation may occur, at least in part, in a different compartment from the classic lysosomal site of protein degradation

  11. MOLECULAR DYNAMICS STUDY OF CYTOCHROME C – LIPID COMPLEXES

    V. Trusova

    2017-10-01

    Full Text Available The interactions between a mitochondrial hemoprotein cytochrome c (cyt c and the model lipid membranes composed of zwitterionic lipid phosphatidylcholine (PC and anionic lipids phosphatidylglycerol (PG, phosphatidylserine (PS or cardiolipin (CL were studied using the method of molecular dynamics. It was found that cyt c structure remains virtually unchanged in the protein complexes with PC/PG or PC/PS bilayers. In turn, protein binding to PC/CL bilayer is followed by the rise in cyt c radius of gyration and root-mean-square fluctuations. The magnitude of these changes was demonstrated to increase with the anionic lipid content. The revealed effect was interpreted in terms of the partial unfolding of polypeptide chain in the region Ala15-Leu32, widening of the heme crevice and enhancement of the conformational fluctuations in the region Pro76-Asp93 upon increasing the CL molar fraction from 5 to 25%. The results obtained seem to be of utmost importance in the context of amyloidogenic propensity of cyt c.

  12. Taxonomic relationships among Phenacomys voles as inferred by cytochrome b

    Bellinger, M.R.; Haig, S.M.; Forsman, E.D.; Mullins, T.D.

    2005-01-01

    Taxonomic relationships among red tree voles (Phenacomys longicaudus longicaudus, P. l. silvicola), the Sonoma tree vole (P. pomo), the white-footed vole (P. albipes), and the heather vole (P. intermedius) were examined using 664 base pairs of the mitochondrial cytochrome b gene. Results indicate specific differences among red tree voles, Sonoma tree voles, white-footed voles, and heather voles, but no clear difference between the 2 Oregon subspecies of red tree voles (P. l. longicaudus and P. l. silvicola). Our data further indicated a close relationship between tree voles and albipes, validating inclusion of albipes in the subgenus Arborimus. These 3 congeners shared a closer relationship to P. intermedius than to other arvicolids. A moderate association between porno and albipes was indicated by maximum parsimony and neighbor-joining phylogenetic analyses. Molecular clock estimates suggest a Pleistocene radiation of the Arborimus clade, which is concordant with pulses of diversification observed in other murid rodents. The generic rank of Arborimus is subject to interpretation of data.

  13. Stability enhancement of cytochrome c through heme deprotonation and mutations.

    Sonoyama, Takafumi; Hasegawa, Jun; Uchiyama, Susumu; Nakamura, Shota; Kobayashi, Yuji; Sambongi, Yoshihiro

    2009-01-01

    The chemical denaturation of Pseudomonas aeruginosa cytochrome c(551) variants was examined at pH 5.0 and 3.6. All variants were stabilized at both pHs compared with the wild-type. Remarkably, the variants carrying the F34Y and/or E43Y mutations were more stabilized than those having the F7A/V13M or V78I ones at pH 5.0 compared with at pH 3.6 by ~3.0-4.6 kJ/mol. Structural analyses predicted that the side chains of introduced Tyr-34 and Tyr-43 become hydrogen donors for the hydrogen bond formation with heme 17-propionate at pH 5.0, but less efficiently at pH 3.6, because the propionate is deprotonated at the higher pH. Our results provide an insight into a stabilization strategy for heme proteins involving variation of the heme electronic state and introduction of appropriate mutations.

  14. Multifunctional Cytochrome c: Learning New Tricks from an Old Dog.

    Alvarez-Paggi, Damián; Hannibal, Luciana; Castro, María A; Oviedo-Rouco, Santiago; Demicheli, Veronica; Tórtora, Veronica; Tomasina, Florencia; Radi, Rafael; Murgida, Daniel H

    2017-11-08

    Cytochrome c (cyt c) is a small soluble heme protein characterized by a relatively flexible structure, particularly in the ferric form, such that it is able to sample a broad conformational space. Depending on the specific conditions, interactions, and cellular localization, different conformations may be stabilized, which differ in structure, redox properties, binding affinities, and enzymatic activity. The primary function is electron shuttling in oxidative phosphorylation, and is exerted by the so-called native cyt c in the intermembrane mitochondrial space of healthy cells. Under pro-apoptotic conditions, however, cyt c gains cardiolipin peroxidase activity, translocates into the cytosol to engage in the intrinsic apoptotic pathway, and enters the nucleus where it impedes nucleosome assembly. Other reported functions include cytosolic redox sensing and involvement in the mitochondrial oxidative folding machinery. Moreover, post-translational modifications such as nitration, phosphorylation, and sulfoxidation of specific amino acids induce alternative conformations with differential properties, at least in vitro. Similar structural and functional alterations are elicited by biologically significant electric fields and by naturally occurring mutations of human cyt c that, along with mutations at the level of the maturation system, are associated with specific diseases. Here, we summarize current knowledge and recent advances in understanding the different structural, dynamic, and thermodynamic factors that regulate the primary electron transfer function, as well as alternative functions and conformations of cyt c. Finally, we present recent technological applications of this moonlighting protein.

  15. Impact of fasting followed by short-term exposure to interleukin-6 on cytochrome P450 mRNA in mice.

    Rasmussen, Martin Krøyer; Bertholdt, Lærke; Gudiksen, Anders; Pilegaard, Henriette; Knudsen, Jakob G

    2018-01-05

    The gene expression of the cytochrome P450 (CYP) enzyme family is regulated by numerous factors. Fasting has been shown to induce increased hepatic CYP mRNA in both humans and animals. However, the coordinated regulation of CYP, CYP-regulating transcription factors, and transcriptional co-factors in the liver linking energy metabolism to detoxification has never been investigated. Interleukin-6 (IL-6) has been suggested to be released during fasting and has been shown to regulate CYP expression. The present study investigated the hepatic mRNA content of selected CYP, AhR, CAR, PXR and PPARα in mice fasted for 18h and subsequently exposed to IL-6. Furthermore, the impact of fasting on PGC-1α, HNF-4α, SIRT1 and SIRT3 mRNA was examined. Fasting induced a marked increase in Cyp2b10, Cyp2e1 and Cyp4a10 mRNA, while CYP1a1, Cyp1a2, Cyp2a4 and Cyp3a11 mRNA levels remained unchanged. In accordance, the mRNA levels of CAR and PPARα were also increased with fasting. The PGC-1α, SIRT1 and SIRT3 mRNA levels were also increased after fasting, while the HNF-4α mRNA levels remained unchanged. In mice subjected to IL-6 injection, the fasting-induced PXR, PPARα and PGC-1α mRNA responses were lower than after saline injection. In conclusion, fasting was demonstrated to be a strong inducer of hepatic CYP mRNA as well as selected transcription factors controlling the expression of the investigated CYP. Moreover, the mRNA levels of transcriptional co-factors acting as energy sensors and co-factors for CYP regulation was also increased in the liver, suggesting crosstalk at the molecular level between regulation of energy metabolism and detoxification. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Human cytochrome-P450 enzymes metabolize N-(2-methoxyphenyl)hydroxylamine, a metabolite of the carcinogens o-anisidine and o-nitroanisole, thereby dictating its genotoxicity.

    Naiman, Karel; Martínková, Markéta; Schmeiser, Heinz H; Frei, Eva; Stiborová, Marie

    2011-12-24

    N-(2-Methoxyphenyl)hydroxylamine is a component in the human metabolism of two industrial and environmental pollutants and bladder carcinogens, viz. 2-methoxyaniline (o-anisidine) and 2-methoxynitrobenzene (o-nitroanisole), and it is responsible for their genotoxicity. Besides its capability to form three deoxyguanosine adducts in DNA, N-(2-methoxyphenyl)-hydroxylamine is also further metabolized by hepatic microsomal enzymes. To investigate its metabolism by human hepatic microsomes and to identify the major microsomal enzymes involved in this process are the aims of this study. N-(2-Methoxyphenyl)hydroxylamine is metabolized by human hepatic microsomes predominantly to o-anisidine, one of the parent carcinogens from which N-(2-methoxyphenyl)hydroxylamine is formed, while o-aminophenol and two N-(2-methoxyphenyl)hydroxylamine metabolites, whose exact structures have not been identified as yet, are minor products. Selective inhibitors of microsomal CYPs, NADPH:CYP reductase and NADH:cytochrome-b(5) reductase were used to characterize human liver microsomal enzymes reducing N-(2-methoxyphenyl)hydroxylamine to o-anisidine. Based on these studies, we attribute the main activity for this metabolic step in human liver to CYP3A4, 2E1 and 2C (more than 90%). The enzymes CYP2D6 and 2A6 also partake in this N-(2-methoxyphenyl)hydroxylamine metabolism in human liver, but only to ∼6%. Among the human recombinant CYP enzymes tested in this study, human CYP2E1, followed by CYP3A4, 1A2, 2B6 and 2D6, were the most efficient enzymes metabolizing N-(2-methoxyphenyl)hydroxylamine to o-anisidine. The results found in this study indicate that genotoxicity of N-(2-methoxyphenyl)hydroxylamine is dictated by its spontaneous decomposition to nitrenium/carbenium ions generating DNA adducts, and by its susceptibility to metabolism by CYP enzymes. Copyright © 2011 Elsevier B.V. All rights reserved.

  17. Congener-specific metabolism and sequestration of dioxin-like compounds by cytochrome P450 1A induced in the liver of crows from Tokyo, Japan

    Watanabe, M.; Iwata, H.; Tanabe, S. [Ehime Univ., Matsuyama (Japan); Yoneda, K.; Hashimoto, T. [Japan Wildlife Research Center, Tokyo (Japan)

    2004-09-15

    Jungle crow (JC; Corvus macrorhynchos) is a useful bioindicator for monitoring contaminants in urban areas, because this species is residential, occupies a same habitat as human, and feeds variety of foods including domestic waste and garbage. Therefore, JCs may accumulate environmental contaminants such as polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and coplanar polychlorinated biphenyls (Co-PCBs), which are released by human activities. Induction of cytochrome P450 (CYP) 1A is a responsive mechanism elicited by exposure to dioxinlike compounds including PCDDs/DFs and Co-PCBs. Toxicokinetic behavior of dioxin-like compounds in organisms is controlled by excretion, metabolism and absorption. These processes are, at least partly, dependent on CYP1A expression in addition to chemical structure and number of chlorine substitution of each congener. Low chlorinated congeners such as 2378-T{sub 4}CDD, 2378- T{sub 4}CDF, 12378-P{sub 5}CDD and 33'44'-PCB were easily metabolized by CYP1A1/2 in rat liver microsomes. PCDDs/DFs accumulate in hepatic tissue to a greater extent than adipose tissue in rats and mice. Recent study using transgenic CYP1A2 knockout mice demonstrated that CYP1A2 is responsible for the sequestration of 2378-T{sub 4}CDD and 23478-P{sub 5}CDF in hepatic tissue. Therefore, CYP1A is considered as a key factor responsible for toxicokinetics of dioxin-like compounds. However, there's no comprehensive data on the contribution of CYP1A to the toxicokinetics of dioxin-like congeners in wild populations. In this study, we investigated contamination levels of PCDDs/DFs and Co-PCBs in liver and breast muscle of JCs from Tokyo, Japan, and interactions of dioxin-like congeners with hepatic CYP to elucidate congener-specific toxicokinetics related to CYP expression in JC.

  18. Altered cytochrome P450 activities and expression levels in the liver and intestines of the monosodium glutamate-induced mouse model of human obesity.

    Tomankova, Veronika; Liskova, Barbora; Skalova, Lenka; Bartikova, Hana; Bousova, Iva; Jourova, Lenka; Anzenbacher, Pavel; Ulrichova, Jitka; Anzenbacherova, Eva

    2015-07-15

    Cytochromes P450 (CYPs) are enzymes present from bacteria to man involved in metabolism of endogenous and exogenous compounds incl. drugs. Our objective was to assess whether obesity leads to changes in activities and expression of CYPs in the mouse liver, small intestine and colon. An obese mouse model with repeated injection of monosodium glutamate (MSG) to newborns was used. Controls were treated with saline. All mice were sacrificed at 8 months. In the liver and intestines, levels of CYP mRNA and proteins were analyzed using RT-PCR and Western blotting. Activities of CYP enzymes were measured with specific substrates of human orthologous forms. At the end of the experiment, body weight, plasma insulin and leptin levels as well as the specific content of hepatic CYP enzymes were increased in obese mice. Among CYP enzymes, hepatic CYP2A5 activity, protein and mRNA expression increased most significantly in obese animals. Higher activities and protein levels of hepatic CYP2E1 and 3A in the obese mice were also found. No or a weak effect on CYPs 2C and 2D was observed. In the small intestine and colon, no changes of CYP enzymes were detected except for increased expression of CYP2E1 and decreased expression of CYP3A mRNAs in the colon of the obese mice. Results of our study suggest that the specific content and activities of some liver CYP enzymes (especially CYP2A5) can be increased in obese mice. Higher activity of CYP2A5 (CYP2A6 human ortholog) could lead to altered metabolism of drug substrates of this enzyme (valproic acid, nicotine, methoxyflurane). Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Cytochrome P450 1A1 (CYP1A1) protects against nonalcoholic fatty liver disease caused by Western diet containing benzo[a]pyrene in mice.

    Uno, Shigeyuki; Nebert, Daniel W; Makishima, Makoto

    2018-03-01

    The Western diet contributes to nonalcoholic fatty liver disease (NAFLD) pathogenesis. Benzo[a]pyrene (BaP), a prototypical environmental pollutant produced by combustion processes, is present in charcoal-grilled meat. Cytochrome P450 1A1 (CYP1A1) metabolizes BaP, resulting in either detoxication or metabolic activation in a context-dependent manner. To elucidate a role of CYP1A1-BaP in NAFLD pathogenesis, we compared the effects of a Western diet, with or without oral BaP treatment, on the development of NAFLD in Cyp1a1(-/-) mice versus wild-type mice. A Western diet plus BaP induced lipid-droplet accumulation in liver of Cyp1a1(-/-) mice, but not wild-type mice. The hepatic steatosis observed in Cyp1a1(-/-) mice was associated with increased cholesterol, triglyceride and bile acid levels. Cyp1a1(-/-) mice fed Western diet plus BaP had changes in expression of genes involved in bile acid and lipid metabolism, and showed no increase in Cyp1a2 expression but did exhibit enhanced Cyp1b1 mRNA expression, as well as hepatic inflammation. Enhanced BaP metabolic activation, oxidative stress and inflammation may exacerbate metabolic dysfunction in liver of Cyp1a1(-/-) mice. Thus, Western diet plus BaP induces NAFLD and hepatic inflammation in Cyp1a1(-/-) mice in comparison to wild-type mice, indicating a protective role of CYP1A1 against NAFLD pathogenesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

  20. Hepatic Complications of Anorexia Nervosa.

    Rosen, Elissa; Bakshi, Neeru; Watters, Ashlie; Rosen, Hugo R; Mehler, Philip S

    2017-11-01

    Anorexia nervosa (AN) has the highest mortality rate of all psychiatric illnesses due to the widespread organ dysfunction caused by the underlying severe malnutrition. Starvation causes hepatocyte injury and death leading to a rise in aminotransferases. Malnutrition-induced hepatitis is common among individuals with AN especially as body mass index decreases. Acute liver failure associated with coagulopathy and encephalopathy can rarely occur. Liver enzymes may also less commonly increase as part of the refeeding process due to hepatic steatosis and can be distinguished from starvation hepatitis by the finding of a fatty liver on ultrasonography. Individuals with AN and starvation-induced hepatitis are at increased risk of hypoglycemia due to depleted glycogen stores and impaired gluconeogenesis. Gastroenterology and hepatology consultations are often requested when patients with AN and signs of hepatitis are hospitalized. It should be noted that additional laboratory testing, imaging, or liver biopsy all have low diagnostic yield, are costly, and potentially invasive, therefore, not generally recommended for diagnostic purposes. While the hepatitis of AN can reach severe levels, a supervised increase in caloric intake and a return to a healthy body weight often quickly lead to normalization of elevated aminotransferases caused by starvation.