Genetics of Nevirapine Metabolic Pathways at Steady State in HIV-Infected Cambodians

ABSTRACT Nevirapine is metabolized by several hepatic cytochrome P450 (CYP) isoforms to generate four primary hydroxylated metabolites: 2-hydroxynevirapine, 3-hydroxynevirapine, 8-hydroxynevirapine, and 12-hydroxynevirapine. The present study characterized associations between genetic polymorphisms and metabolite ratios in HIV-infected Cambodians. We demonstrate associations between CYP2B6 polymorphisms and metabolite ratios for both 3-hydroxynevirapine and 8-hydroxynevirapine, suggesting involvement of CYP2B6 in generating these metabolites.

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Five genetic polymorphisms of cytochrome P450 enzymes in the Czech non-Roma and Czech Roma population samples

Drug Metabolism and Personalized Therapy ◽

10.1515/dmdi-2020-0103 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Lucie Dlouhá ◽

Věra Adámková ◽

Lenka Šedová ◽

Věra Olišarová ◽

Jaroslav A. Hubáček ◽

...

Keyword(s):

Cytochrome P450 ◽

Genetic Polymorphisms ◽

Metabolic Pathways ◽

Cytochromes P450 ◽

Taqman Assay ◽

Cytochrome P450 Enzymes ◽

Roma Population ◽

Czech Population ◽

Genotype Frequencies ◽

Pcr Rflp

AbstractObjectivesCytochromes P450 play a role in human drugs metabolic pathways and their genes are among the most variable in humans. The aim of this study was to analyze genotype frequencies of five common polymorphisms of cytochromes P450 in Roma/Gypsy and Czech (non-Roma) population samples with Czech origin.MethodsRoma/Gypsy (n=302) and Czech subjects (n=298) were genotyped for CYP1A2 (rs762551), CYP2A6 (rs4105144), CYP2B6 (rs3745274) and CYP2D6 (rs3892097; rs1065852) polymorphisms using PCR-RFLP or Taqman assay.ResultsWe found significant allelic/genotype differences between ethnics in three genes. For rs3745274 polymorphism, there was increased frequency of T allele carriers in Roma in comparison with Czech population (53.1 vs. 43.7%; p=0.02). For rs4105144 (CYP2A6) there was higher frequency of T allele carriers in Roma in comparison with Czech population (68.7 vs. 49.8%; p<0.0001). For rs3892097 (CYP2D6) there was more carriers of the A allele between Roma in comparison with Czech population (39.2 vs. 38.2%; p=0.048). Genotype/allelic frequencies of CYP2D6 (rs1065852) and CYP1A2 (rs762551) variants did not significantly differ between the ethnics.ConclusionsThere were significant differences in allelic/genotype frequencies of some, but not all cytochromes P450 polymorphisms between the Czech Roma/Gypsies and Czech non-Roma subjects.

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Exploring the Metabolism of Loxoprofen in Liver Microsomes: The Role of Cytochrome P450 and UDP-Glucuronosyltransferase in Its Biotransformation

Pharmaceutics ◽

10.3390/pharmaceutics10030112 ◽

2018 ◽

Vol 10 (3) ◽

pp. 112 ◽

Cited By ~ 6

Author(s):

Riya Shrestha ◽

Pil Cho ◽

Sanjita Paudel ◽

Aarajana Shrestha ◽

Mi Kang ◽

...

Keyword(s):

Cytochrome P450 ◽

Active Metabolite ◽

Experimental Studies ◽

Liver Microsomes ◽

Cytochrome P450s ◽

Hydroxylated Metabolites ◽

Udp Glucuronosyltransferase ◽

Cyp Isoforms ◽

Propionic Acid Derivative

Loxoprofen, a propionic acid derivative, non-steroidal anti-inflammatory drug (NSAID) is a prodrug that is reduced to its active metabolite, trans-alcohol form (Trans-OH) by carbonyl reductase enzyme in the liver. Previous studies demonstrated the hydroxylation and glucuronidation of loxoprofen. However, the specific enzymes catalyzing its metabolism have yet to be identified. In the present study, we investigated metabolic enzymes, such as cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), which are involved in the metabolism of loxoprofen. Eight microsomal metabolites of loxoprofen were identified, including two alcohol metabolites (M1 and M2), two mono-hydroxylated metabolites (M3 and M4), and four glucuronide conjugates (M5, M6, M7, and M8). Based on the results for the formation of metabolites when incubated in dexamethasone-induced microsomes, incubation with ketoconazole, and human recombinant cDNA-expressed cytochrome P450s, we identified CYP3A4 and CYP3A5 as the major CYP isoforms involved in the hydroxylation of loxoprofen (M3 and M4). Moreover, we identified that UGT2B7 is the major UGT isoform catalyzing the glucuronidation of loxoprofen and its alcoholic metabolites. Further experimental studies should be carried out to determine the potency and toxicity of these identified metabolites of loxoprofen, in order to fully understand of mechanism of loxoprofen toxicity.

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Organohalogens and their hydroxylated metabolites in the blood of pigs from an open waste dumping site in south India: Association with hepatic cytochrome P450

Environmental Research ◽

10.1016/j.envres.2015.02.012 ◽

2015 ◽

Vol 138 ◽

pp. 255-263 ◽

Cited By ~ 11

Author(s):

Hazuki Mizukawa ◽

Kei Nomiyama ◽

Tatsuya Kunisue ◽

Michio X. Watanabe ◽

Annamalai Subramanian ◽

...

Keyword(s):

Cytochrome P450 ◽

South India ◽

Dumping Site ◽

Hydroxylated Metabolites ◽

Hepatic Cytochrome

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Effects of Andrographis paniculata crude extract and Andrographolide on hepatic cytochrome P450 mRNA expression and monooxygenase activities

Planta Medica ◽

10.1055/s-0028-1084228 ◽

2008 ◽

Vol 74 (09) ◽

Author(s):

D Pekthong ◽

N Blanchard ◽

C Abadie ◽

A Bonet ◽

B Heyd ◽

...

Keyword(s):

Cytochrome P450 ◽

Mrna Expression ◽

Crude Extract ◽

Andrographis Paniculata ◽

Hepatic Cytochrome

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P.615 Effect of cocaine self-administration on hepatic cytochrome P450 activity in the rat model of drug addiction

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2020.09.453 ◽

2020 ◽

Vol 40 ◽

pp. S350-S351

Author(s):

J. Jastrzębska ◽

R. Pukło ◽

M. Frankowska ◽

M. Filip ◽

W.A. Daniel

Keyword(s):

Cytochrome P450 ◽

Drug Addiction ◽

Rat Model ◽

Self Administration ◽

Cytochrome P450 Activity ◽

P450 Activity ◽

Hepatic Cytochrome

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Cytochrome P450-dependent biotransformation capacities in embryonic, juvenile and adult stages of zebrafish (Danio rerio)—a state-of-the-art review

Archives of Toxicology ◽

10.1007/s00204-021-03071-7 ◽

2021 ◽

Author(s):

Ann-Kathrin Loerracher ◽

Thomas Braunbeck

Keyword(s):

Cytochrome P450 ◽

Phase I ◽

Mrna Expression ◽

Danio Rerio ◽

Developmental Stages ◽

State Of The Art ◽

Adverse Outcome Pathway ◽

Zebrafish Embryos ◽

Toxicological Studies ◽

Cyp Isoforms

AbstractGiven the strong trend to implement zebrafish (Danio rerio) embryos as translational model not only in ecotoxicological, but also toxicological testing strategies, there is an increasing need for a better understanding of their capacity for xenobiotic biotransformation. With respect to the extrapolation of toxicological data from zebrafish embryos to other life stages or even other organisms, qualitative and quantitative differences in biotransformation pathways, above all in cytochrome P450-dependent (CYP) phase I biotransformation, may lead to over- or underestimation of the hazard and risk certain xenobiotic compounds may pose to later developmental stages or other species. This review provides a comprehensive state-of-the-art overview of the scientific knowledge on the development of the CYP1-4 families and corresponding phase I biotransformation and bioactivation capacities in zebrafish. A total of 68 publications dealing with spatiotemporal CYP mRNA expression patterns, activities towards mammalian CYP-probe substrates, bioactivation and detoxification activities, as well as metabolite profiling were analyzed and included in this review. The main results allow for the following conclusions: (1) Extensive work has been done to document mRNA expression of CYP isoforms from earliest embryonic stages of zebrafish, but juvenile and adult zebrafish have been largely neglected so far. (2) There is insufficient understanding of how sex- and developmental stage-related differences in expression levels of certain CYP isoforms may impact biotransformation and bioactivation capacities in the respective sexes and in different developmental stages of zebrafish. (3) Albeit qualitatively often identical, many studies revealed quantitative differences in metabolic activities of zebrafish embryos and later developmental stages. However, the actual relevance of age-related differences on the outcome of toxicological studies still needs to be clarified. (4) With respect to current remaining gaps, there is still an urgent need for further studies systematically assessing metabolic profiles and capacities of CYP isoforms in zebrafish. Given the increasing importance of Adverse Outcome Pathway (AOP) concepts, an improved understanding of CYP capacities appears essential for the interpretation and outcome of (eco)toxicological studies.

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