ArticleDrug metabolism and disposition: the biological fate of chemicals2012
Effects of the CYP2B6*6 allele on catalytic properties and inhibition of CYP2B6 in vitro: implication for the mechanism of reduced efavirenz metabolism and other CYP2B6 substrates in vivo.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 68 citations in OpenAlex.
- Pharmacogenetic Influence on Stereoselective Steady-State Disposition of Bupropion.Drug metabolism and disposition: the biological fate of chemicals · 2024Trial
- Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition.Clinical pharmacology and therapeutics · 2019Trial
- Effects of Genetic Polymorphisms of CYP2B6 on the Pharmacokinetics of Bupropion and Hydroxybupropion in Healthy Chinese Subjects.Medical science monitor : international medical journal of experimental and clinical research · 2018Trial
- Inhibition of Cytochrome P450 2B6 Activity by Voriconazole Profiled Using Efavirenz Disposition in Healthy Volunteers.Antimicrobial agents and chemotherapy · 2016Trial
- Methadone Pharmacogenetics: CYP2B6 Polymorphisms Determine Plasma Concentrations, Clearance, and Metabolism.Anesthesiology · 2015Trial
- Population pharmacogenetic-based pharmacokinetic modeling of efavirenz, 7-hydroxy- and 8-hydroxyefavirenz.Journal of clinical pharmacology · 2014Trial
- CYP2B6 pharmacogenetics-based in vitro-in vivo extrapolation of efavirenz clearance by physiologically based pharmacokinetic modeling.Drug metabolism and disposition: the biological fate of chemicals · 2013Trial
- Effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites: exploration of a novel CYP2B6 phenotyping index.British journal of clinical pharmacology · 2013Trial
- Systematic review on genetic polymorphisms associated with idiosyncratic drug-induced liver injury (iDILI): iDILInet as an interactive visualization tool.Acta pharmaceutica Sinica. B · 2026Article
- miR-375 protects against acetaminophen-induced acute liver failure by orchestrating pharmacogene expression.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Translating pharmacogenomic sequencing data into drug response predictions-How to interpret variants of unknown significance.British journal of clinical pharmacology · 2025Review
- Article
- Influence of CYP450 Enzymes and ABCB1 Polymorphisms on Clopidogrel Response in Moroccan Patients with Acute Coronary Syndromes.Pharmacogenomics and personalized medicine · 2023Article
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- CYP2B6 allelic variants and non-genetic factors influence CYP2B6 enzyme function.Scientific reports · 2022Article
- The reference liver-CYP450 and UGT enzymes in healthy donor and metastatic livers: the impact of genotype.Pharmacological reports : PR · 2022Article
- Warfarin Pharmacogenomics for Precision Medicine in Real-Life Clinical Practice in Southern Africa: Harnessing 73 Variants in 29 Pharmacogenes.Omics : a journal of integrative biology · 2022Article
- Physiologically Based Pharmacokinetic Modeling of Bupropion and Its Metabolites in a CYP2B6 Drug-Drug-Gene Interaction Network.Pharmaceutics · 2021Article
- The far-reaching HAND of cART: cART effects on astrocytes.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2021Review
- Sources of Interindividual Variability.Methods in molecular biology (Clifton, N.J.) · 2021Article
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
The mechanism by which CYP2B6*6 allele alters drug metabolism in vitro and in vivo is not fully understood. To test the hypothesis that altered substrate binding and/or catalytic properties contribute to its functional consequences, efavirenz 8-hydroxylation and bupropion 4-hydroxylation were determined in CYP2B6.1 and CYP2B6.6 proteins expressed without and with cytochrome b5 (Cyt b5) and in human liver microsomes (HLMs) obtained from liver tissues genotyped for the CYP2B6*6 allele. The susceptibility of the variant protein to inhibition was also tested in HLMs. Significantly higher V(max) and K(m) values for 8-hydroxyefavirenz formation and ∼2-fold lower intrinsic clearance (Cl(int)) were noted in expressed CYP2B6.6 protein (-b5) compared with that of CYP2B6.1 protein (-b5); this effect was abolished by Cyt b5. The V(max) and Cl(int) values for 4-hydroxybupropion formation were significantly higher in CYP2B6.6 than in CYP2B6.1 protein, with no difference in K(m), whereas coexpression with Cyt b5 reversed the genetic effect on these kinetic parameters. In HLMs, CYP2B6*6/*6 genotype was associated with markedly lower V(max) (and moderate increase in K(m)) and thus lower Cl(int) values for efavirenz and bupropion metabolism, but no difference in catalytic properties was noted between CYP2B6*1/*1 and CYP2B6*1/*6 genotypes. Inhibition of efavirenz 8-hydroxylation by voriconazole was significantly greater in HLMs with the CYP2B6*6 allele (K(i) = 1.6 ± 0.8 μM) than HLMs with CYP2B6*1/*1 genotype (K(i) = 3.0 ± 1.1 μM). In conclusion, our data suggest the CYP2B6*6 allele influences metabolic activity by altering substrate binding and catalytic activity in a substrate- and Cyt b5-dependent manner. It may also confer susceptibility to inhibition.
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