ArticleDrug metabolism and disposition: the biological fate of chemicals2009
Decreased susceptibility of the cytochrome P450 2B6 variant K262R to inhibition by several clinically important drugs.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 30 citations in OpenAlex.
- Article
- CYP2B6 allelic variants and non-genetic factors influence CYP2B6 enzyme function.Scientific reports · 2022Article
- PharmGKB summary: sertraline pathway, pharmacokinetics.Pharmacogenetics and genomics · 2020Article
- The Prevalence ofOsong public health and research perspectives · 2018Article
- Functional importance of a peripheral pocket in mammalian cytochrome P450 2B enzymes.Archives of biochemistry and biophysics · 2015Article
- Isoniazid mediates the CYP2B6*6 genotype-dependent interaction between efavirenz and antituberculosis drug therapy through mechanism-based inactivation of CYP2A6.Antimicrobial agents and chemotherapy · 2014Article
- Impact of CYP polymorphisms, ethnicity and sex differences in metabolism on dosing strategies: the case of efavirenz.European journal of clinical pharmacology · 2014Review
- Functional characterization of cytochromes P450 2B from the desert woodrat Neotoma lepida.Toxicology and applied pharmacology · 2014Article
- The effect of ritonavir on human CYP2B6 catalytic activity: heme modification contributes to the mechanism-based inactivation of CYP2B6 and CYP3A4 by ritonavir.Drug metabolism and disposition: the biological fate of chemicals · 2013Article
- Structural and thermodynamic basis of (+)-α-pinene binding to human cytochrome P450 2B6.Journal of the American Chemical Society · 2013Article
- Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance.Frontiers in genetics · 2013Article
- Alcohol consumption effect on antiretroviral therapy and HIV-1 pathogenesis: role of cytochrome P450 isozymes.Expert opinion on drug metabolism & toxicology · 2012Review
- Investigation by site-directed mutagenesis of the role of cytochrome P450 2B4 non-active-site residues in protein-ligand interactions based on crystal structures of the ligand-bound enzyme.The FEBS journal · 2012Article
- 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.Drug metabolism and disposition: the biological fate of chemicals · 2012Article
- Effects of sertraline on the pharmacokinetics of bupropion and its major metabolite, hydroxybupropion, in mice.European journal of drug metabolism and pharmacokinetics · 2012Article
- Potential contribution of cytochrome P450 2B6 to hepatic 4-hydroxycyclophosphamide formation in vitro and in vivo.Drug metabolism and disposition: the biological fate of chemicals · 2012Article
- Differential effects of ethanol on spectral binding and inhibition of cytochrome P450 3A4 with eight protease inhibitors antiretroviral drugs.Alcoholism, clinical and experimental research · 2011Article
- Polymorphic variants of cytochrome P450 2B6 (CYP2B6.4-CYP2B6.9) exhibit altered rates of metabolism for bupropion and efavirenz: a charge-reversal mutation in the K139E variant (CYP2B6.8) impairs formation of a functional cytochrome p450-reductase complex.The Journal of pharmacology and experimental therapeutics · 2011Article
- Crystal structure of a cytochrome P450 2B6 genetic variant in complex with the inhibitor 4-(4-chlorophenyl)imidazole at 2.0-A resolution.Molecular pharmacology · 2010Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Cytochrome P450 (P450) 2B6 metabolizes a number of clinically relevant drugs and is one of the most highly polymorphic human P450 enzymes, with the Lys(262)-->Arg substitution being especially common in several genetic variants. Therefore, K262R (2B6*4) was created in the CYP2B6dH background (N-terminal-modified and C-terminal His-tagged) and expressed in Escherichia coli. The recombinant CYP2B6dH and K262R were purified and studied to investigate the effect of the Lys(262)-->Arg substitution with six of the most potent drug inhibitors of CYP2B6, namely, clopidogrel, clotrimazole, itraconazole, raloxifene, sertraline, and ticlopidine. K262R showed a >3-fold increase in the K(i) values with clopidogrel, itraconazole, and raloxifene and approximately 6-fold increase in K(i) with sertraline compared with CYP2B6dH. Likewise, K262R showed 2-, 4-, and >20-fold higher K(s) values than CYP2B6dH with clopidogrel, sertraline, and itraconazole, respectively. In contrast, when tested with several known type II inhibitors of CYP2B enzymes, K262R showed a 10-fold lower IC(50) with 4-(phenyl)pyridine and approximately 2-fold lower IC(50) with 4-(4-nitrobenzyl)pyridine or 1-(4-phenyl)benzylimidazole than CYP2B6dH. Subsequent analysis predicted possible in vivo drug-drug interactions between the CYP2B6 substrate efavirenz and drug inhibitors clopidogrel, clotrimazole, itraconazole, sertraline, and ticlopidine. Furthermore, Q172H/K262R (2B6*6), which is the most common genetic variant of CYP2B6 harboring K262R, was created in CYP2B6dH, expressed, purified, and characterized for inhibition. Q172H/K262R showed a >6-fold increase in K(i) with sertraline and clopidogrel compared with CYP2B6dH. The results suggest that individuals, especially homozygotes, with the 2B6*4 or 2B6*6 allele might be less susceptible to drug interactions resulting from P450 inhibition.
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