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Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance

Ulrich M. Zanger, Kathrin Klein

Frontiers in Genetics · 2013

doi:10.3389/fgene.2013.00024

Abstract

Cytochrome P450 2B6 (CYP2B6) belongs to the minor drug metabolizing P450s in human liver. Expression is highly variable both between individuals and within individuals, owing to non-genetic factors, genetic polymorphisms, inducibility, and irreversible inhibition by many compounds. Drugs metabolized mainly by CYP2B6 include artemisinin, bupropion, cyclophosphamide, efavirenz, ketamine, and methadone. CYP2B6 is one of the most polymorphic CYP genes in humans and variants have been shown to affect transcriptional regulation, splicing, mRNA and protein expression, and catalytic activity. Some variants appear to affect several functional levels simultaneously, thus, combined in haplotypes, leading to complex interactions between substrate-dependent and -independent mechanisms. The most common functionally deficient allele is CYP2B6*6 [Q172H, K262R], which occurs at frequencies of 15 to over 60% in different populations. The allele leads to lower expression in liver due to erroneous splicing. Recent investigations suggest that the amino acid changes contribute complex substrate-dependent effects at the activity level, although data from recombinant systems used by different researchers are not well in agreement with each other. Another important variant, CYP2B6*18 [I328T], occurs predominantly in Africans (4-12%) and does not express functional protein. A large number of uncharacterized variants are currently emerging from different ethnicities in the course of the 1000 Genomes Project. The CYP2B6 polymorphism is clinically relevant for HIV-infected patients treated with the reverse transcriptase inhibitor efavirenz, but it is increasingly being recognized for other drug substrates. This review summarizes recent advances on the functional and clinical significance of CYP2B6 and its genetic polymorphism, with particular emphasis on the comparison of kinetic data obtained with different substrates for variants expressed in different recombinant expression systems.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 18, 2026. Paragraph numbers are ours, so an answer can point at one.

INTRODUCTION

The cytochrome P450 (CYP) enzyme CYP2B6 is one of about a dozen human CYPs that are primarily involved in the biotransformation of drugs and other xenobiotics. The CYP2B6 gene and its closely related pseudogene, CYP2B7, are located in a tandem head-to-tail arrangement within a large CYP2 gene cluster on the long arm of chromosome 19 (; Figure 1). The orthologous genes in dog, mouse, and rat are termed CYP2B11, Cyp2b10, and CYP2B1, respectively, but in contrast to other mammalian species, CYP2B6 is the only functional isozyme of its subfamily in humans. Owing to the existence of extensive genetic polymorphism as well as strong inhibitors and inducers, its activity is highly variable in the population. For some clinically used drugs including the antiretroviral agents efavirenz and nevirapine, CYP2B6 single nucleotide polymorphisms have been shown to be useful predictors of pharmacokinetics and drug response (reviewed in;; ). However, recent data indicate that pharmacogenetic mechanisms are complex, appear on several levels of gene expression from the initial mRNA transcript to splice variants (pre-mRNA splicing and mRNA expression) to altered proteins, and affect function in various ways including substrate-dependent and substrate-independent effects. Several previous reviews are available that cover the biochemical pharmacology, molecular genetics, and pharmacogenetics of this enzyme at various degrees of detail. The purpose of this review is to summarize recent advances in areas that have an impact on variable expression of CYP2B6 and the mechanisms and impact of CYP2B6 polymorphism, as observed by various in vitro approaches as well as in in vivo studies, and to discuss their functional and clinical implications.

VARIABILITY OF EXPRESSION AND TRANSCRIPTIONAL REGULATION

Cytochrome P450 2B6 is primarily expressed in the liver where its contribution to the total microsomal P450 pool has been estimated to be within a range of about 1–10%, with a large inter-individual variability at protein level of roughly 100-fold (see for review and references therein). Although some earlier studies reported expression in only a fraction of human livers, newer studies with better antibodies found CYP2B6 to be present in all investigated human adult liver samples while up to one-third of pediatric samples contained no detectable protein. In the latter study, ontogenic differences were studied in liver microsomes from 217 pediatric liver donors. Hepatic median CYP2B6 protein levels were about twofold higher in the period between birth and 30 days postnatal compared to fetal samples, and protein levels varied already over 25-fold in both of these age groups. Maturation effects may further depend on genotype, as suggested in a study on HIV-infected children treated with efavirenz.

One of the most important factors contributing to intra- as well as inter-individual variability is enzyme induction, i.e., de novo protein synthesis following exposure to certain chemicals. Regulation of CYP2B gene expression represents the archetypal example of enzyme induction. Human CYP2B6 is strongly inducible by several drugs including “classical” inducers such as rifampicin, phenytoin, and phenobarbital involving a so-called phenobarbital-responsive enhancer module (PBREM) at -1.7 kb of the CYP2B6 gene promoter, and a distal xenobiotics-responsive enhancer module (XREM, -8.5 kb), to which pregnane X receptor (PXR, NR1I2) and/or constitutive androstane receptor (CAR, NR1I3) bind to mediate increased transcription. Since other CYPs are regulated by overlapping sets of nuclear receptors, CYP2B6 is often co-induced with CYP2C enzymes and CYP3A4. CYP2B6 inducers identified to date include cyclophosphamide, hyperforin, artemisinin antimalarials, carbamazepine, metamizole, ritonavir, the insect repellent N,N-diethyl-m-toluamide (DEET; ), statins, efavirenz. Interestingly, in the latter study, gender influenced the inducibility of efavirenz 8-hydroxylation, which was higher in women than in the men. In addition to therapeutic drugs, pesticides were found to be powerful inducers of CYP2B6 and other CYPs through interaction with both PXR and CAR. Induction of CYP2B6 and other cytochromes P450 and its clinical consequences has been reviewed by others.

Sex differences in liver expression have been observed in a number of studies. Females liver donors had higher amounts of CYP2B6 mRNA (3.9-fold), protein (1.7-fold), and enzyme activity (1.6-fold) compared to male subjects in a study of 80 ethnically mixed samples. In a study with 235 Caucasian liver donors, female samples had 1.6-fold higher expression level of CYP2B6 mRNA, however, this difference did not translate into higher protein and activity levels and no sex difference was found when only liver donors without presurgical drug exposure were considered. Discrepant effects of sex on pharmacokinetics of CYP2B6 substrates, which may be due to other confounders such as age or smoking status, were also found in vivo. Higher bupropion hydroxylation rates were found in adolescent females compared to males but not in adults. For efavirenz, several studies reported elevated plasma concentrations in female compared to male patients, which is in contrast to the above-mentioned in vitro findings and may be explained by other factors such as differences in body fat content and distribution. The influence of age on CYP2B6 expression may also depend on sex, as only males showed a significant increase of liver CYP2B6 at higher age.

Besides liver, CYP2B6 is also consistently expressed in different parts of respiratory and gastrointestinal tracts, including lung and nasal mucosa, and also in skin and the kidneys. The significance of CYP2B6 in these extrahepatic tissues is currently unknown, but it should be remembered that the enzyme is probably the most important one for many environmental toxins such as pesticides, and its presence in tissues with barrier function may thus contribute substantially to protection against these chemicals. In addition, the presence of CYP2B6 in brain has been demonstrated in human and primate brain tissue samples and smoking, alcohol consumption, and genetic polymorphism have been suggested to contribute to its variability in this organ. In general, CYP levels in extrahepatic tissues are far below those of liver, but the localization to specific regions in the brain may contribute to the activation or inactivation of centrally acting drugs and to neurological side effects of certain medications or abused drugs, e.g., “ecstasy” [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), see below]. This may also explain why efficacy for some centrally acting drugs is not well correlated to their plasma levels. The potential role of brain-expressed CYPs including CYP2B6 in the biotransformation of centrally acting drugs has been reviewed by others.

THE CHEMICAL INTERACTION PROFILE OF CYP2B6

Recent studies have revealed crystal structures of the CYP2B6 wild-type and K262R variant in complex with various inhibitors at providing first views into its active site and its plasticity to adopt different conformations when binding different ligands. Substrates of CYP2B6 are usually fairly lipophilic, neutral or weakly basic non-planar molecules with one or two hydrogen bond acceptors. The CYP2B6 substrate selectivity comprises many diverse chemicals, including not only clinically used drugs but also many environmental chemicals such as pesticides. Therapeutically important drugs metabolized primarily by CYP2B6 include the prodrug cyclophosphamide, which is converted to the direct precursor of the cytotoxic metabolites, phosphoramide mustard and acrolein, by 4-hydroxylation, the non-nucleoside reverse transcriptase inhibitor (NNRTI), efavirenz, which is 8-hydroxylated to become pharmacologically inactive, the atypical antidepressant and smoking cessation agent bupropion, which is converted to pharmacologically active hydroxybupropion, the anesthetics propofol and ketamine, the analgesic pethidine (meperidine; ); the μ-opioid receptor agonist, methadone, the antimalarial artemisinin, among numerous additional metabolic pathways of other drugs, to which CYP2B6 contributes in part, such as the antiretroviral, nevirapine, and many others. Metabolic pathways suitable as probe for CYP2B6 activity include S-mephenytoin N-demethylation, bupropion hydroxylation and efavirenz, based on in vitro investigations.

Endogenous substances metabolized by the enzyme include arachidonic acid, lauric acid, 17beta-estradiol, estrone, ethinylestradiol, and testosterone 16α- and 16β-hydroxylation.

Cytochrome P450 2B6 furthermore participates in the biotransformation of the abused drug “ecstasy” (N-methyl-3,4-methylenedioxymethamphetamine, MDMA), which is N-demethylated leading to potentially neurotoxic metabolites. It also plays a minor role in nicotine metabolism. CYP2B6 has furthermore been found to be of importance in the metabolism of pesticides and other environmental chemicals and pollutants. In particular the bioactivating oxidation of the organophosphorus insecticides chlorpyrifos and methyl parathion to their more toxic oxon metabolites is mainly catalyzed by CYP2B6, a public health concern due to their worldwide use and documented human exposures. Further environmental substrates are the insecticide and endocrine disruptor methoxychlor, the extensively used insect repellent N,N-diethyl-m-toluamide, profenofos and other pesticides, as well as the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; ), aflatoxin B1, and others.

Several structurally unrelated drugs have been shown to inhibit CYP2B6 and many of them do that in a mechanism-based, irreversible manner. The thienopyridine derivatives clopidogrel and ticlopidine are prodrugs that selectively inhibit platelet aggregation and have been in clinical use for the prevention of atherothrombotic events for several years. Both of them are potent mechanism-based inhibitors of CYP2B6. The established anticancer agent, thioTEPA (N,N′,N′′-triethylenethiophosphoramide) was also found to be a highly selective and mechanism-based CYP2B6 inhibitor. A comparison of several selective inhibitors revealed that 2-phenyl-2-(1-piperidinyl)propane is probably the most selective CYP2B6 inhibitor in vitro. Recent in vitro observations identified the progesterone receptor antagonist, mifepristone (RU486; ); the anti-Parkinsonian agent selegiline (the R-enantiomer of deprenyl; ), methadone, and tamoxifen as potent mechanism-based inhibitors. In vivo drug–drug interactions have been reported, for example, between thioTEPA and cyclophosphamide, clopidogrel and bupropion, voriconazole and efavirenz, clopidogrel and efavirenz, and between ticlopidine and ketamine. Furthermore, certain non-pharmaceutical compounds like particular benzylpyridine derivatives have been characterized as very potent inhibitors of CYP2B6 and have been utilized for structural modeling experiments.

PHARMACOGENETICS OF CYP2B6

The CYPalleles website1 currently lists 37 distinct star-alleles, i.e., gene haplotypes with a distinct variant amino acid sequence or with demonstrated functional effect (last accessed: February 21st, 2013). More than 30 amino acid-changing single-nucleotide polymorphisms (SNPs) occur in different combinations and together with additional non-coding variants and many more SNPs not yet assigned to particular haplotypes. The worldwide variations in SNP frequencies have been reviewed recently. Table 1 lists the most important variants in terms of frequency and functional impact and summarizes updated structural, functional, and frequency information for different ethnicities. In addition to the CYPallele website, further valuable information about CYP2B6 SNPs and pharmacogenetics are available on the websites of The Pharmacogenomics Knowledgebase2, the NCBI portal for short genetic variations, dbSNP3, the 1000 Genomes Catalog of Human Genetic Variation4, as well as the NHLBI exome sequencing project5.

CYP2B6*6 AND EFAVIRENZ: IN VIVO, EX VIVO, IN VITRO

The most common variant allele in all populations studied to date harbors two amino acid changes, Q172H and K262R, and is termed CYP2B6*6. This haplotype occurs in about 15 to over 60% of individuals, depending on ethnicity (Table 1). Although additional variants occur in the promoter and in introns, their functional impact appears to be of limited relevance and will not be further discussed here.

Since the discovery that CYP2B6 is the major enzyme for efavirenz 8-hydroxylation, pharmacogenetic studies have linked the Q172H variant to elevated plasma concentrations of efavirenz, indicating decreased enzyme function in vivo. This finding has been reproduced manifold in different ethnicities throughout the world (summarized by; ). Three CYP2B6 polymorphisms, 15631G>T, 21011T>C, and an intron 3 SNP rs4803419, were also shown to be associated with efavirenz pharmacokinetics at genome wide significance.

The potent first-generation NNRTI of HIV-1 is recommended as initial therapy with two NRTIs in highly active antiretroviral therapy (HAART) regimes, but patients with subtherapeutic plasma concentrations can develop resistance and treatment failure, whereas those with too high plasma levels are at increased risk of central nervous system (CNS) side effects, which can lead to treatment discontinuation in a fraction of patients. Q172H variant was furthermore associated with increased neurotoxicity and other CNS side effects with HAART-induced liver injury, and with efavirenz treatment discontinuation and the associated risk of developing drug resistance. Importantly, compound heterozygotes of 516T and another low activity allele (e.g., *11, *18, *27, *28) also predict high efavirenz plasma levels. In prospective, genotype-based dose adjustment studies the therapeutic dose of efavirenz could be successfully reduced and CNS-related side effects decreased. Using pharmacokinetic modeling and simulation it was suggested that a priori dose reduction in homozygous CYP2B6*6 patients would maintain drug exposure within the therapeutic range in this group of patients.

The in vitro data that have accumulated over the years on the CYP2B6*6 allele draw a more complex picture with functional consequences on various levels including pre-mRNA splicing, protein expression, as well as substrate-dependent changes in enzyme activity and different sensitivity toward irreversible inhibition. While early studies using recombinantly expressed enzyme variants found higher 7-ethoxycoumarin O-deethylase activity for the Q172H variant, in genotyped human livers (ex vivo), the *6 allele has been associated with approximately 50–75% decreased protein levels. An explanation for decreased protein expression was provided based on the observation that the c.516G>T SNP coding for Q172H in exon 4 (rs3745274, Table 1) was correlated to increased amounts of a hepatic splice variant that lacked exons 4–6, and concurrently to decreased amounts of the normal functional transcript. Recombinant expression of minigene constructs in mammalian cells proved that the c.516G>T variant was causally involved in erroneous splicing and lower expression of functional mRNA and protein. It has been hypothesized that binding of splice factors to an exonic splicing enhancer(s) located in exon 4 could be affected by the variant. Although reduced expression in liver appears to satisfactorily explain increased efavirenz plasma concentrations in individuals with *6/*6 genotype, recent in vitro data of expressed variants seem to indicate that the amino acid substitutions contribute to changes in catalytic activity of the enzyme. Structurally this is not easy to comprehend, because the Q172H and Lys262Arg amino acid changes occur in regions of the protein that are not directly located at the active site or that have been identified as substrate recognition sites (Figure 2).

Concerning efavirenz and also other substrates, the available in vitro data are however, not well in agreement with each other. Table 2 summarizes kinetic parameters for bupropion and efavirenz for CYP2B6 enzyme variants obtained from different recombinant expression systems. Using Escherichia coli expression system, purified six N-terminally truncated expressed variants to homogeneity and reconstituted them with NADPH:cytochrome 450 reductase (POR) at a molar ratio of 1:2 and measured efavirenz and bupropion kinetics. Using Sf9 insect cell cotransfection, CYP2B6.1, 2B6.4 and 2B6.6 were expressed in the presence of 10-fold excess of POR, i.e., under saturating conditions, to measure efavirenz kinetics. Another study determined both bupropion and efavirenz kinetics in protein preparations also derived from insect cells in the presence or absence of cytochrome b5 (CYB5) but at somewhat more variable ratios in regard to POR. used the COS-1 expression system, where P450 monooxygenase activity is supported by endogenously expressed POR, to determine bupropion and efavirenz kinetics for several novel CYP2B6 variants in comparison to the known variants 2B6.1, 2B6.5, and 2B6.6.

The compilation of data in Table 2 shows that differences between the variants were masked by differences between the expression systems. For example, efavirenz Km was moderately decreased (58%) for COS-1 cell-expressed 2B6.6 compared to 2B6.1 but moderately larger for both insect cell-expressed proteins. The E. coli-expressed variant showed, however, 27-fold increased Km. While the COS-1 proteins had almost identical Vmax, one of the insect cellproteins had decreased Vmax (81%), while the other had increased activity (133%). Again, the E. coli-expressed variant showed the biggest difference of almost sixfold higher activity for the variant. Similar discrepancies, albeit less dramatic, were found with bupropion as substrate (Table 2).

This data-comparison illustrates the problems that still exist with recombinant P450 expression systems, and particularly for CYP2B6, which appears to be an enzyme that sensibly reacts with activity changes to expression conditions. It is difficult to pin down the reasons for these differences exactly. Reconstitution of recombinant or even purified P450 with POR and CYB5 is a non-trivial problem especially if different protein variants shall be compared for quantitative kinetic parameters. Reconstitution under saturating conditions with respect to electron donators, e.g., at a POR:P450 ratio of 10, is a straightforward practical way, but in hepatocytes, POR is stoichiometrically underrepresented (ratio about 1:10) and may be limiting for monooxygenase activity. Enzyme variants may interact differently with the electron donors and catalytic differences could thus depend on reconstitution conditions. In addition, N-terminal modifications required to achieve high expression in E. coli may interact with the DNA-polymorphisms to be analyzed. In the COS-cell system, on the other hand, the POR:P450 ratio can neither be controlled nor quantified because expression of P450 is too low for spectral quantitation.

Taken together, the data from expression systems indicated that catalytic differences may exist between CYP2B6.6 and CYP2B6.1. However, except for the E. coli study, the differences were rather modest and at present it cannot be concluded with certainty whether the CYP2B6.6 variant is catalytically more or less active compared to the wild-type, atleast for bupropion and efavirenz. Taken all evidence together, the decrease in hepatic expression due to erroneous splicing caused by the c.516G>T SNP most plausibly explains most of the phenotypic in vivo activity differences observed with efavirenz and bupropion.

CYP2B6*6 SNP-related functional differences were also observed with inhibitors. In contrast to the wild-type enzyme the recombinantly expressed K262R variant was not inactivated by efavirenz, but both enzymes were irreversibly inhibited by 8-hydroxyefavirenz. Lower susceptibility to inhibition of the K262R variant and the CYP2B6.6 double variant compared to CYP2B6.1 was also found with respect to sertraline and clopidogrel, as well as several other potent drug inhibitors of CYP2B6. These data indicate a role of genetic polymorphisms in drug–drug interaction sensitivity of CYP2B6, a finding that warrants further investigation in vivo.

OTHER CYP2B6 VARIANTS AND OTHER SUBSTRATES – IN VITRO STUDIES

The two amino acid changes that together constitute the *6 allele also occur in isolation, although at much lower frequencies (;; Table 1). In most pharmacogenetic studies they are not being determined and functional data is therefore rare, especially concerning *9. Data from recombinant systems as well as liver data suggest that the K262R variant possesses catalytic activities similar to the wild-type enzyme, although with different substrates moderately increased or decreased activity was observed (Tables 2 and 3;; ). The allele with amino acid change [R487C] in exon 9 (*5 variant; Table 1) expresses very low levels of protein which does not translate into similarly reduced activities as measured with bupropion as well as efavirenz. The variant was shown to have higher specific activity compared to wild-type. In human liver, this leads to partial compensation of low expression, finally resulting in a phenotype with moderately decreased activity with bupropion and efavirenz in vivo. This explains why CYP2B6*5 was not associated with efavirenz pharmacokinetics in HIV patients.

The second most important functionally deficient allele is CYP2B6*18 (c.983C>T [I328T]), which occurs predominantly in African subjects with allele frequencies of 4–11%. The I328T variant expressed no detectable protein or activity toward bupropion, 7-ethoxy-4-trifluoromethylcoumarin (7-EFC), selegiline and artemether in COS-1 cells whereas a partially defective protein was expressed in insect cells. This demonstrates another example for expression system-dependent differences. Most likely the 2B6.18 variant is temperature-sensitive and thus able to be expressed at the lower temperature (27°C) of insect cell culture but not at 37°C. Interestingly, the I328T+Q172H double variant expressed partially functional protein in HEK293 cells and in yeast, indicating that Q172H can stabilize the I328T variant. The *18 allele is thus phenotypically a null allele, at least in vitro with some substrates. This is supported by many in vivo studies (see below).

At least 12 additional null or low-activity alleles have been described and analyzed with various substrates. Although they are rather rare in all investigated populations they may have profound effects on drug metabolism if present in compound heterozygous genotypes, e.g., in combination with *6 or *18. The CYP2B6*22 allele is a gain-of-function variant associated with increased transcription in vitro and with increased activity in vivo. It was shown that a -82T>C exchange alters the TATA-box into a functional CCAAT/enhancer-binding protein binding site that causes increased transcription from an alternative downstream initiation site. Interestingly, the -82T>C polymorphism also confers synergistically enhanced CYP2B6 inducibility by the PXR ligand rifampicin in human primary hepatocytes.

New variants are discovered preferentially in previously uncharacterized ethnic groups. described two novel combinations of known amino acid variants in a Colombian population. Structural variants including a novel CYP2B6/2B7P1 duplicated fusion allele (CYP2B6*30) were found when individuals from various ethnicities were screened for copy number variations. Furthermore, three novel and five previously uncharacterized amino acid variants in different combinations (CYP2B6*33 to *37) were identified by resequencing the CYP2B6 gene in a Rwandese cohort of HIV-1-infected patients. The variants were then functionally studied by COS-1 cell expression and by in silico prediction tools. At least four of the variants were shown to result in complete or almost complete loss of function with bupropion and efavirenz as substrates. The detailed comparison of in vitro functionality of the variants with in silico prediction tools including a thorough substrate docking simulation analysis points at the challenge to deal with the hundreds of new variants that exist in all populations as currently uncovered by next generation sequencing approaches and large scale population projects (see links above).

CLINICAL STUDIES WITH DIFFERENT DRUGS

The widely used anticancer and immunosuppressant prodrug cyclophosphamide depends on bioactivation to 4-hydroxycyclophosphamide for cytotoxic activity. Bioactivation is highly variable in cancer patients and has been attributed mainly to CYP2B6 in vitro and in vivo with contributions from CYP2C19 and CYP3A4. The case of cyclophosphamide 4-hydroxylation deserves particular attention, as it exemplifies substrate-dependent effects of CYP2B6 pharmacogenetics. Cyclophosphamide 4-hydroxylation was initially reported to be enhanced in livers genotyped CYP2B6*6/*6, which was confirmed in several later in vivo studies. However, other in vivo studies analyzing pharmacokinetics or clinical outcome also presented contradictory or negative results. In vitro, insect cell-expressed recombinant CYP2B6.4 [K262R] had lower activity for cyclophosphamide 4-hydroxylation. The CYP2B6.4 and CYP2B6.6 variants thus display mirror-inverted catalytic activities toward efavirenz and cyclophosphamide, in that the former variant is the catalytically more active one with efavirenz, whereas the opposite is true for the latter variant (Table 3). A direct comparison of catalytic properties of the two variants with the reference enzyme expressed in insect cells supports this inverse behavior of the two variants toward these two substrates. Interestingly, several studies associated other variants including CYP2B6*4, *5, *8,and *9 with lower 4-OH cyclophosphamide formation in vivo or with worse outcome. Taken together, the data concerning cyclophosphamide from both in vivo and in vitro indicate that CYP2B6 polymorphism plays a role, although the studies are so far not yet conclusive. This may be explained by different study size design as well as lack of consistency in allele definition and genotype information among studies.

In addition to efavirenz, CYP2B6 genotype also affects plasma levels of the antiretroviral drug nevirapine. The impact of the CYP2B6 516G>T polymorphism on nevirapine exposure was confirmed and quantified in a pharmacometric analysis of nevirapine plasma concentrations from 271 patients genotyped for 198 SNPs in 45 ADME (absorption, distribution, metabolism, and excretion) genes and covariates. Moreover, nevirapine-related cutaneous adverse events, which are most likely major histocompatibility complex (MHC) class I-mediated, were significantly influenced by CYP2B6 polymorphism while hepatic side effects, most likely MHC class II-mediated, were unaffected by CYP2B6.

CYP2B6 allele variants were also investigated in the context of the synthetic μ-opioid receptor agonist, methadone, which is metabolized by CYPs 3A4/5, 2B6, and 2D6, and used as a maintenance treatment for opioid addiction. In *6/*6 carriers (S)-methadone plasma levels were increased leading to potentially higher risk of severe cardiac arrhythmias and methadone associated deaths. Methadone dose requirement for effective treatment of opioid addiction was shown to be significantly reduced in carriers of this genotype.

CONCLUSION

The polymorphism of the CYP2B6 gene has initially been studied by reverse genetics approach, i.e., starting from the identification of genetic variants in DNA and liver samples, followed by in vitro characterization of genotyped livers and expressed variant proteins. Clinical studies have then contributed to identify the variants that are important in vivo, and in vitro studies are again needed to identify and mechanistically explain causal variants. Nevertheless, CYP2B6 pharmacogenetics has yet to be fully explored, especially with respect to combined effects of the involved variants on both expression and catalytic properties, the latter of which additionally depend on the substrate. While the relevance for HIV-1 therapy with efavirenz is well established and translational approaches have already been clinically tested, an increasing number of studies suggest clinical relevance for additional drug substrates.

Conflict of Interest Statement

Ulrich M. Zanger is a named coinventor of a patent on the detection of specific CYP2B6 polymorphisms for diagnostic purposes. Kathrin Klein declares no conflict of interest.

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  18. 18.

    Croom E. L. Stevens J. C. Hines R. N. Wallace A. D. Hodgson E. (2009 ). Human hepatic CYP2B6 developmental expression: the impact of age and genotype. Biochem. Pharmacol. 78 184–190

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    Desta Z. Moaddel R. Ogburn E. T. Xu C. Ramamoorthy A. Venkata S. L. V. (2012 ). Stereoselective and regiospecific hydroxylation of ketamine and norketamine. Xenobiotica 42 1076–1087

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    Faucette S. R. Zhang T.-C. Moore R. Sueyoshi T. Omiecinski C. J. LeCluyse E. L. (2007 ). Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers. J. Pharmacol. Exp. Ther. 320 72–80

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    Feidt D. M. Klein K. Hofmann U. Riedmaier S. Knobeloch D. Thasler W. E. (2010 ). Profiling induction of cytochrome p450 enzyme activity by statins using a new liquid chromatography-tandem mass spectrometry cocktail assay in human hepatocytes. Drug Metab. Dispos. 38 1589–1597

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    Ferguson C. S. Tyndale R. F. (2011 ). Cytochrome P450 enzymes in the brain: emerging evidence of biological significance. Trends Pharmacol. Sci. 32 708–714

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    Gatanaga H. Hayashida T. Tsuchiya K. Yoshino M. Kuwahara T. Tsukada H. (2007 ). Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P450 2B6 *6 and *26. Clin. Infect. Dis. 45 1230–1237

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    Gatanaga H. Oka S. (2009 ). Successful genotype-tailored treatment with small-dose efavirenz. AIDS 23 433–434

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    Gervot L. Rochat B. Gautier J. C. Bohnenstengel F. Kroemer H. de Berardinis V. (1999 ). Human CYP2B6: expression, inducibility and catalytic activities. Pharmacogenetics 9 295–306

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    Goodwin B. Moore L. B. Stoltz C. M. McKee D. D. Kliewer S. A. (2001 ). Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor. Mol. Pharmacol. 60 427–431

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    Haas D. W. Ribaudo H. J. Kim R. B. Tierney C. Wilkinson G. R. Gulick R. M. (2004 ). Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 18 2391–2400

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    Habtewold A. Amogne W. Makonnen E. Yimer G. Riedel K.-D. Ueda N. (2011 ). Long-term effect of efavirenz autoinduction on plasma/peripheral blood mononuclear cell drug exposure and CD4 count is influenced by UGT2B7 and CYP2B6 genotypes among HIV patients. J. Antimicrob. Chemother. 66 2350–2361

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  44. 44.

    Harleton E. Webster M. Bumpus N. N. Kent U. M. Rae J. M. Hollenberg P. F. (2004 ). Metabolism of N,N′,N′′-triethylenethiophosphoramide by CYP2B1 and CYP2B6 results in the inactivation of both isoforms by two distinct mechanisms. J. Pharmacol. Exp. Ther. 310 1011–1019

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  45. 45.

    Helsby N. Tingle M. (2011 ). The importance of correct assignment of CYP2B6 genetic variants with respect to cyclophosphamide metabolizer status. Am. J. Hematol. 86 383–384; author reply 384.

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    Helsby N. A. Hui C.-Y. Goldthorpe M. A. Coller J. K. Soh M. C. Gow P. J. (2010 ). The combined impact of CYP2C19 and CYP2B6 pharmacogenetics on cyclophosphamide bioactivation. Br. J. Clin. Pharmacol. 70 844–853

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  47. 47.

    Hesse L. M. He P. Krishnaswamy S. Hao Q. Hogan K. von Moltke L. L. (2004 ). Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes. Pharmacogenetics 14 225–238

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    Hesse L. M. Venkatakrishnan K. Court M. H. von Moltke L. L. Duan S. X. Shader R. I. (2000 ). CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Drug Metab. Dispos. 28 1176–1183

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  49. 49.

    Hodgson E. Rose R. L. (2007 ). The importance of cytochrome P450 2B6 in the human metabolism of environmental chemicals. Pharmacol. Ther. 113 420–428

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  50. 50.

    Hoffman S. M. Nelson D. R. Keeney D. S. (2001 ). Organization, structure and evolution of the CYP2 gene cluster on human chromosome 19. Pharmacogenetics 11 687–698

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    Hofmann M. H. Blievernicht J. K. Klein K. Saussele T. Schaeffeler E. Schwab M. (2008 ). Aberrant splicing caused by single nucleotide polymorphism c.516G>T [Q172H], a marker of CYP2B6*6, is responsible for decreased expression and activity of CYP2B6 in liver. J. Pharmacol. Exp. Ther. 325 284–292

    Not in our library10.1124/jpet.107.133306

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    Holzinger E. R. Grady B. Ritchie M. D. Ribaudo H. J. Acosta E. P. Morse G. D. (2012 ). Genome-wide association study of plasma efavirenz pharmacokinetics in AIDS Clinical Trials Group protocols implicates several CYP2B6 variants. Pharmacogenet. Genomics 22 858–867

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    Honda M. Muroi Y. Tamaki Y. Saigusa D. Suzuki N. Tomioka Y. (2011 ). Functional characterization of CYP2B6 allelic variants in demethylation of antimalarial artemether. Drug Metab. Dispos. 39 1860–1865

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    Hsyu P. H. Singh A. Giargiari T. D. Dunn J. A. Ascher J. A. Johnston J. A. (1997 ). Pharmacokinetics of bupropion and its metabolites in cigarette smokers versus nonsmokers. J. Clin. Pharmacol. 37 737–743

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    Huang Z. Roy P. Waxman D. J. (2000 ). Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamide. Biochem. Pharmacol. 59 961–972

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  56. 56.

    Huitema A. D. Kerbusch T. Tibben M. M. Rodenhuis S. Beijnen J. H. (2000 ). Reduction of cyclophosphamide bioactivation by thioTEPA: critical sequence-dependency in high-dose chemotherapy regimens. Cancer Chemother. Pharmacol. 46 119–127

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    Humphrey W. Dalke A. Schulten K. (1996 ). VMD: visual molecular dynamics. J. Mol. Graph. 14, 33–38 27–28

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    Jeong S. Nguyen P. D. Desta Z. (2009 ). Comprehensive in vitro analysis of voriconazole inhibition of eight cytochrome P450 (CYP) enzymes: major effect on CYPs 2B6, 2C9, 2C19, and 3A. Antimicrob. Agents Chemother. 53 541–551

    Not in our library10.1128/aac.01123-08

  59. 59.

    Jiang F. Desta Z. Shon J.-H. Yeo C.-W. Kim H.-S. Liu K.-H. (2012 ). Effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl-metabolites: exploration of a novel CYP2B6 phenotyping index. Br. J. Clin. Pharmacol. 75 244–253

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  60. 60.

    Jinno H. Tanaka-Kagawa T. Ohno A. Makino Y. Matsushima E. Hanioka N. (2003 ). Functional characterization of cytochrome P450 2B6 allelic variants. Drug Metab. Dispos. 31 398–403

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  61. 61.

    Joy M. S. La M. Wang J. Bridges A. S. Hu Y. Hogan S. L. (2012 ). Cyclophosphamide and 4-hydroxycyclophosphamide pharmacokinetics in patients with glomerulonephritis secondary to lupus and small vessel vasculitis. Br. J. Clin. Pharmacol. 74 445–455

    Not in our library10.1111/j.1365-2125.2012.04223.x

  62. 62.

    Kharasch E. D. Mitchell D. Coles R. Blanco R. (2008 ). Rapid clinical induction of hepatic cytochrome P4502B6 activity by ritonavir. Antimicrob. Agents Chemother. 52 1663–1669

    Not in our library10.1128/aac.01600-07

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    King J. Aberg J. A. (2008 ). Clinical impact of patient population differences and genomic variation in efavirenz therapy. AIDS 22 1709–1717

    Not in our library10.1097/qad.0b013e32830163ad

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    Klein K. Lang T. Saussele T. Barbosa-Sicard E. Schunck W.-H. Eichelbaum M. (2005 ). Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional variants, and possible implications for anti-HIV therapy with efavirenz. Pharmacogenet. Genomics 15 861–873

    Not in our library10.1097/01213011-200512000-00004

  65. 65.

    Ko J. W. Desta Z. Flockhart D. A. (1998 ). Human N-demethylation of (S)-mephenytoin by cytochrome P450s 2C9 and 2B6. Drug Metab. Dispos. 26 775–778

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    Korhonen L. E. Turpeinen M. Rahnasto M. Wittekindt C. Poso A. Pelkonen O. (2007 ). New potent and selective cytochrome P450 2B6 (CYP2B6) inhibitors based on three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis. Br. J. Pharmacol. 150 932–942

    Not in our library10.1038/sj.bjp.0707173

  67. 67.

    Kreth K. Kovar K. Schwab M. Zanger U. M. (2000 ). Identification of the human cytochromes P450 involved in the oxidative metabolism of “Ecstasy”-related designer drugs. Biochem. Pharmacol. 59 1563–1571

    Not in our library10.1016/s0006-2952(00)00284-7

  68. 68.

    Lamba V. Lamba J. Yasuda K. Strom S. Davila J. Hancock M. L. (2003 ). Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive androstane receptor) expression. J. Pharmacol. Exp. Ther. 307 906–922

    Not in our library10.1124/jpet.103.054866

  69. 69.

    Lang T. Klein K. Fischer J. Nüssler A. K. Neuhaus P. Hofmann U. (2001 ). Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics 11 399–415

    Not in our library10.1097/00008571-200107000-00004

  70. 70.

    Lang T. Klein K. Richter T. Zibat A. Kerb R. Eichelbaum M. (2004 ). Multiple novel nonsynonymous CYP2B6 gene polymorphisms in Caucasians: demonstration of phenotypic null alleles. J. Pharmacol. Exp. Ther. 311 34–43

    Not in our library10.1124/jpet.104.068973

  71. 71.

    Leclerc J. Tournel G. Courcot-Ngoubo Ngangue E. Pottier N. Lafitte J.-J. Jaillard S. (2010 ). Profiling gene expression of whole cytochrome P450 superfamily in human bronchial and peripheral lung tissues: differential expression in non-small cell lung cancers. Biochimie 92 292–306

    Not in our library10.1016/j.biochi.2009.12.007

  72. 72.

    Lehr T. Yuan J. Hall D. Zimdahl-Gelling H. Schaefer H. G. Staab A. (2011 ). Integration of absorption, distribution, metabolism, and elimination genotyping data into a population pharmacokinetic analysis of nevirapine. Pharmacogenet. Genomics 21 721–730

    Not in our library10.1097/fpc.0b013e32834a522e

  73. 73.

    Levran O. Peles E. Hamon S. Randesi M. Adelson M. Kreek M. J. (2011 ). CYP2B6 SNPs are associated with methadone dose required for effective treatment of opioid addiction. Addict. Biol.

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    Lewis D. F. Lake B. G. Dickins M. Eddershaw P. J. Tarbit M. H. Goldfarb P. S. (1999 ). Molecular modelling of CYP2B6, the human CYP2B isoform, by homology with the substrate-bound CYP102 crystal structure: evaluation of CYP2B6 substrate characteristics, the cytochrome b5 binding site and comparisons with CYP2B1 and CYP2B4. Xenobiotica 29 361–393

    Not in our library10.1080/004982599238560

  75. 75.

    Lewis D. F. V. Lake B. G. Dickins M. (2004 ). Substrates of human cytochromes P450 from families CYP1 and CYP2: analysis of enzyme selectivity and metabolism. Drug Metab. Drug Interact. 20 111–142

    Not in our library10.1515/dmdi.2004.20.3.111

  76. 76.

    Li H. Ferguson S. S. Wang H. (2010 ). Synergistically enhanced CYP2B6 inducibility between a polymorphic mutation in CYP2B6 promoter and pregnane X receptor activation. Mol. Pharmacol. 78 704–713

    Not in our library10.1124/mol.110.065185

  77. 77.

    Li J. Menard V. Benish R. L. Jurevic R. J. Guillemette C. Stoneking M. (2012 ). Worldwide variation in human drug-metabolism enzyme genes CYP2B6 and UGT2B7: implications for HIV/AIDS treatment. Pharmacogenomics 13 555–570

    Not in our library10.2217/pgs.11.160

  78. 78.

    Lin H. L. Zhang H. Hollenberg P. F. (2009 ). Metabolic activation of mifepristone (RU486) by mammalian P450s and the mechanism-based inactivation of human CYP2B6. J. Pharmacol. Exp. Ther. 329 26–37

    Not in our library10.1124/jpet.108.148536

  79. 79.

    Liu P. Foster G. LaBadie R. R. Gutierrez M. J. Sharma A. (2008 ). Pharmacokinetic interaction between voriconazole and efavirenz at steady state in healthy male subjects. J. Clin. Pharmacol. 48 73–84

    Not in our library10.1177/0091270007309703

  80. 80.

    Lubomirov R. Colombo S. di Iulio J. Ledergerber B. Martinez R. Cavassini M. (2011 ). Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study. J. Infect. Dis. 203 246–257

    Not in our library10.1093/infdis/jiq043

  81. 81.

    Lubomirov R. di Iulio J. Fayet A. Colombo S. Martinez R. Marzolini C. (2010 ). ADME pharmacogenetics: investigation of the pharmacokinetics of the antiretroviral agent lopinavir coformulated with ritonavir. Pharmacogenet. Genomics 20 217–230

    Not in our library10.1097/fpc.0b013e328336eee4

  82. 82.

    Mahungu T. Smith C. Turner F. Egan D. Youle M. Johnson M. (2009 ). Cytochrome P450 2B6 516G–>T is associated with plasma concentrations of nevirapine at both 200 mg twice daily and 400 mg once daily in an ethnically diverse population. HIV Med. 10 310–317

    Not in our library10.1111/j.1468-1293.2008.00689.x

  83. 83.

    Maimbo M. Kiyotani K. Mushiroda T. Masimirembwa C. Nakamura Y. (2011 ). CYP2B6 genotype is a strong predictor of systemic exposure to efavirenz in HIV-infected Zimbabweans. Eur. J. Clin. Pharmacol. 68 267–271

    Not in our library10.1007/s00228-011-1118-0

  84. 84.

    Martis S. Mei H. Vijzelaar R. Edelmann L. Desnick R. J. Scott S. A. (2012 ). Multi-ethnic cytochrome-P450 copy number profiling: novel pharmacogenetic alleles and mechanism of copy number variation formation. Pharmacogenomics J.

    Not in our library

  85. 85.

    Mehlotra R. K. Bockarie M. J. Zimmerman P. A. (2007 ). CYP2B6 983T>C polymorphism is prevalent in West Africa but absent in Papua New Guinea: implications for HIV/AIDS treatment. Br. J. Clin. Pharmacol. 64 391–395

    Not in our library10.1111/j.1365-2125.2007.02884.x

  86. 86.

    Melanson S. E. F. Stevenson K. Kim H. Antin J. H. Court M. H. Ho V. T. (2010 ). Allelic variations in CYP2B6 and CYP2C19 and survival of patients receiving cyclophosphamide prior to myeloablative hematopoietic stem cell transplantation. Am. J. Hematol. 85 967–971

    Not in our library10.1002/ajh.21889

  87. 87.

    Meyer R. P. Gehlhaus M. Knoth R. Volk B. (2007 ). Expression and function of cytochrome p450 in brain drug metabolism. Curr. Drug Metab. 8 297–306

    Not in our library10.2174/138920007780655478

  88. 88.

    Miksys S. Lerman C. Shields P. G. Mash D. C. Tyndale R. F. (2003 ). Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain. Neuropharmacology 45 122–132

    Not in our library10.1016/s0028-3908(03)00136-9

  89. 89.

    Mo S.-L. Liu Y.-H. Duan W. Wei M. Q. Kanwar J. R. Zhou S.-F. (2009 ). Substrate specificity, regulation, and polymorphism of human cytochrome P450 2B6. Curr. Drug Metab. 10 730–753

    Not in our library10.2174/138920009789895534

  90. 90.

    Mukonzo J. K. Röshammar D. Waako P. Andersson M. Fukasawa T. Milani L. (2009 ). A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans. Br. J. Clin. Pharmacol. 68 690–699

    Not in our library10.1111/j.1365-2125.2009.03516.x

  91. 91.

    Nakajima M. Komagata S. Fujiki Y. Kanada Y. Ebi H. Itoh K. (2007 ). Genetic polymorphisms of CYP2B6 affect the pharmacokinetics/pharmacodynamics of cyclophosphamide in Japanese cancer patients. Pharmacogenet. Genomics 17 431–445

    Not in our library10.1097/fpc.0b013e328045c4fb

  92. 92.

    Nelson D. R. Zeldin D. C. Hoffman S. M. G. Maltais L. J. Wain H. M. Nebert D. W. (2004 ). Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics 14 1–18

    Not in our library10.1097/00008571-200401000-00001

  93. 93.

    Ngaimisi E. Mugusi S. Minzi O. M. Sasi P. Riedel K.-D. Suda A. (2010 ). Long-term efavirenz autoinduction and its effect on plasma exposure in HIV patients. Clin. Pharmacol. Ther. 88 676–684

    Not in our library10.1038/clpt.2010.172

  94. 94.

    Nguyen T.-A. Tychopoulos M. Bichat F. Zimmermann C. Flinois J.-P. Diry M. (2008 ). Improvement of cyclophosphamide activation by CYP2B6 mutants: from in silico to ex vivo. Mol. Pharmacol. 73 1122–1133

    Not in our library10.1124/mol.107.042861

  95. 95.

    Niu R.-J. Zheng Q.-C. Zhang J.-L. Zhang H.-X. (2011 ). Analysis of clinically relevant substrates of CYP2B6 enzyme by computational methods. J. Mol. Model. 17 2839–2846

    Not in our library10.1007/s00894-011-0970-2

  96. 96.

    Nyakutira C. Röshammar D. Chigutsa E. Chonzi P. Ashton M. Nhachi C. (2008 ). High prevalence of the CYP2B6 516G–>T(*6) variant and effect on the population pharmacokinetics of efavirenz in HIV/AIDS outpatients in Zimbabwe. Eur. J. Clin. Pharmacol. 64 357–365

    Not in our library10.1007/s00228-007-0412-3

  97. 97.

    Oda Y. Hamaoka N. Hiroi T. Imaoka S. Hase I. Tanaka K. (2001 ). Involvement of human liver cytochrome P4502B6 in the metabolism of propofol. Br. J. Clin. Pharmacol. 51 281–285

    Not in our library10.1046/j.1365-2125.2001.00344.x

  98. 98.

    Oscarson M. Zanger U. M. Rifki O. F. Klein K. Eichelbaum M. Meyer U. A. (2006 ). Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin. Pharmacol. Ther. 80 440–456

    Not in our library10.1016/j.clpt.2006.08.013

  99. 99.

    Pelkonen O. Turpeinen M. Hakkola J. Honkakoski P. Hukkanen J. Raunio H. (2008 ). Inhibition and induction of human cytochrome P450 enzymes: current status. Arch. Toxicol. 82 667–715

    Not in our library10.1007/s00204-008-0332-8

  100. 100.

    Peltoniemi M. A. Saari T. I. Hagelberg N. M. Reponen P. Turpeinen M. Laine K. (2011 ). Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. Clin. Pharmacol. Ther. 90 296–302

    Not in our library10.1038/clpt.2011.140

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    Penzak S. R. Kabuye G. Mugyenyi P. Mbamanya F. Natarajan V. Alfaro R. M. (2007 ). Cytochrome P450 2B6 (CYP2B6) G516T influences nevirapine plasma concentrations in HIV-infected patients in Uganda. HIV Med. 8 86–91

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    Qin W.-J. Zhang W. Liu Z.-Q. Chen X.-P. Tan Z.-R. Hu D.-L. (2012 ). Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men. Br. J. Clin. Pharmacol. 74 999–1004

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    Rakhmanina N. Y van den Anker J. N. (2010 ). Efavirenz in the therapy of HIV infection. Expert Opin. Drug Metab. Toxicol. 6 95–103

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    Ramírez J. Innocenti F. Schuetz E. G. Flockhart D. A. Relling M. V. Santucci R. (2004 ). CYP2B6, CYP3A4, and CYP2C19 are responsible for the in vitro N-demethylation of meperidine in human liver microsomes. Drug Metab. Dispos. 32 930–936

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    Remmer H. Schoene B. Fleischmann R. A. (1973 ). Induction of the unspecific microsomal hydroxylase in the human liver. Drug Metab. Dispos. 1 224–230

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    Restrepo J. G. Martínez C. García-Agúndez G. Gaviria E. Laguna J. J. García-Martín E. (2011 ). Cytochrome P450 CYP2B6 genotypes and haplotypesin a Colombian population: identification of novel variant CYP2B6 alleles. Pharmacogenet. Genomics 21 773–778

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    Ribaudo H. J. Haas D. W. Tierney C. Kim R. B. Wilkinson G. R. Gulick R. M. (2006 ). Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study. Clin. Infect. Dis. 42 401–407

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    Richter T. Schwab M. Eichelbaum M. Zanger U. M. (2005 ). Inhibition of human CYP2B6 by N,N′,N′ ′-triethylenethiophosphoramide is irreversible and mechanism-based. Biochem. Pharmacol. 69 517–524

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    Roy J.-N. Lajoie J. Zijenah L. S. Barama A. Poirier C. Ward B. J. (2005 ). CYP3A5 genetic polymorphisms in different ethnic populations. Drug Metab. Dispos. 33 884–887

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    Sadee W. Wang D. Papp A. C. Pinsonneault J. K. Smith R. M. Moyer R. A. (2011 ). Pharmacogenomics of the RNA world: structural RNA polymorphisms in drug therapy. Clin. Pharmacol. Ther. 89 355–365

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    Simonsson U. S. H. Jansson B. Hai T. N. Huong D. X. Tybring G. Ashton M. (2003 ). Artemisinin autoinduction is caused by involvement of cytochrome P450 2B6 but not 2C9. Clin. Pharmacol. Ther. 74 32–43

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    Singh G. Saxena N. Aggarwal A. Misra R. (2007 ). Cytochrome P450 polymorphism as a predictor of ovarian toxicity to pulse cyclophosphamide in systemic lupus erythematosus. J. Rheumatol. 34 731–733

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    Smith G. B. J. Bend J. R. Bedard L. L. Reid K. R. Petsikas D. Massey T. E. (2003 ). Biotransformation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in peripheral human lung microsomes. Drug Metab. Dispos. 31 1134–1141

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    Sridar C. Kenaan C. Hollenberg P. F. (2012 ). Inhibition of bupropion metabolism by selegiline: mechanism-based inactivation of human CYP2B6 and characterization of glutathione and peptide adducts. Drug Metab. Dispos. 40 2256–2266

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    Stewart J. J. Berkel H. J. Parish R. C. Simar M. R. Syed A. Bocchini J. A. (2001 ). Single-dose pharmacokinetics of bupropion in adolescents: effects of smoking status and gender. J. Clin. Pharmacol. 41 770–778

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    Sueyoshi T. Kawamoto T. Zelko I. Honkakoski P. Negishi M. (1999 ). The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene. J. Biol. Chem. 274 6043–6046

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    Svensson U. S. Ashton M. (1999 ). Identification of the human cytochrome P450 enzymes involved in the in vitro metabolism of artemisinin. Br. J. Clin. Pharmacol. 48 528–535

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    Takada K. Arefayene M. Desta Z. Yarboro C. H. Boumpas D. T. Balow J. E. (2004 ). Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis. Arthritis Rheum. 50 2202–2210

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    Talakad J. C. Kumar S. Halpert J. R. (2009 ). Decreased susceptibility of the cytochrome P450 2B6 variant K262R to inhibition by several clinically important drugs. Drug Metab. Dispos. 37 644–650

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    Telenti A. Zanger U. M. (2008 ). Pharmacogenetics of anti-HIV drugs. Annu. Rev. Pharmacol. Toxicol. 48 227–256

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    Thelen K. Dressman J. B. (2009 ). Cytochrome P450-mediated metabolism in the human gut wall. J. Pharm. Pharmacol. 61 541–558

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  130. 130.

    Torimoto Y. Kohgo Y. (2008 ). [Cyclophosphamide and CYP2B6]. Gan To Kagaku Ryoho 35 1090–1093

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  131. 131.

    Totah R. A. Sheffels P. Roberts T. Whittington D. Thummel K. Kharasch E. D. (2008 ). Role of CYP2B6 in stereoselective human methadone metabolism. Anesthesiology 108 363–374

    Not in our library10.1097/aln.0b013e3181642938

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    Turpeinen M. Raunio H. Pelkonen O. (2006 ). The functional role of CYP2B6 in human drug metabolism: substrates and inhibitors in vitro, in vivo and in silico. Curr. Drug Metab. 7 705–714

    Not in our library10.2174/138920006778520633

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    Turpeinen M. Tolonen A. Uusitalo J. Jalonen J. Pelkonen O. Laine K. (2005a ). Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. Clin. Pharmacol. Ther. 77 553–559

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    Turpeinen M. Uusitalo J. Jouko U. Jalonen J. Jorma J. Pelkonen O. (2005b ). Multiple P450 substrates in a single run: rapid and comprehensive in vitro interaction assay. Eur. J. Pharm. Sci. 24 123–132

    Not in our library10.1016/j.ejps.2004.10.006

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    Turpeinen M. Zanger U. M. (2012 ). Cytochrome P450 2B6: function, genetics, and clinical relevance. Drug Metabol. Drug Interact. 27 185–197

    Not in our library10.1515/dmdi-2012-0027

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    Walsky R. L. Obach R. S. (2007 ). A comparison of 2-phenyl-2-(1-piperidinyl)propane (ppp), 1,1′,1′′-phosphinothioylidynetrisaziridine (thioTEPA), clopidogrel, and ticlopidine as selective inactivators of human cytochrome P450 2B6. Drug Metab. Dispos. 35 2053–2059

    Not in our library10.1124/dmd.107.015883

  137. 137.

    Wang H. Faucette S. Sueyoshi T. Moore R. Ferguson S. Negishi M. (2003 ). A novel distal enhancer module regulated by pregnane X receptor/constitutive androstane receptor is essential for the maximal induction of CYP2B6 gene expression. J. Biol. Chem. 278 14146–14152

    Not in our library10.1074/jbc.m212482200

  138. 138.

    Wang J. Sönnerborg A. Rane A. Josephson F. Lundgren S. Ståhle L. (2006 ). Identification of a novel specific CYP2B6 allele in Africans causing impaired metabolism of the HIV drug efavirenz. Pharmacogenet. Genomics 16 191–198

    Not in our library10.1097/01.fpc.0000189797.03845.90

  139. 139.

    Wang H. Tompkins L. M. (2008 ). CYP2B6: new insights into a historically overlooked cytochrome P450 isozyme. Curr. Drug Metab. 9 598–610

    Not in our library10.2174/138920008785821710

  140. 140.

    Ward B. A. Gorski J. C. Jones D. R. Hall S. D. Flockhart D. A. Desta Z. (2003 ). The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J. Pharmacol. Exp. Ther. 306 287–300

    Not in our library10.1124/jpet.103.049601

  141. 141.

    Watanabe T. Sakuyama K. Sasaki T. Ishii Y. Ishikawa M. Hirasawa N. (2010 ). Functional characterization of 26 CYP2B6 allelic variants (CYP2B6.2-CYP2B6.28, except CYP2B6.22). Pharmacogenet. Genomics 20 459–462

    Not in our library10.1097/fpc.0b013e32833bba0e

  142. 142.

    Wilderman P. R. Halpert J. R. (2012 ). Plasticity of CYP2B enzymes: structural and solution biophysical methods. Curr. Drug Metab. 13 167–176

    Not in our library10.2174/138920012798918417

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    Wyen C. Hendra H. Siccardi M. Platten M. Jaeger H. Harrer T. (2011 ). Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens. J. Antimicrob. Chemother. 66 2092–2098

    Not in our library10.1093/jac/dkr272

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    Xie H. Griskevicius L. Ståhle L. Hassan Z. Yasar U. Rane A. (2006 ). Pharmacogenetics of cyclophosphamide in patients with hematological malignancies. Eur. J. Pharm. Sci. 27 54–61

    Not in our library10.1016/j.ejps.2005.08.008

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    Xie H.-J. Yasar U. Lundgren S. Griskevicius L. Terelius Y. Hassan M. (2003 ). Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation. Pharmacogenomics J. 3 53–61

    Not in our library10.1038/sj.tpj.6500157

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    Xu C. Ogburn E. T. Guo Y. Desta Z. (2012 ). 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 Metab. Dispos. 40 717–725

    Not in our library10.1124/dmd.111.042416

  147. 147.

    Yamanaka H. Nakajima M. Fukami T. Sakai H. Nakamura A. Katoh M. (2005 ). CYP2A6 AND CYP2B6 are involved in nornicotine formation from nicotine in humans: interindividual differences in these contributions. Drug Metab. Dispos. 33 1811–1818

    Not in our library10.1124/dmd.105.006254

  148. 148.

    Yamazaki H. Inoue K. Hashimoto M. Shimada T. (1999 ). Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes. Arch. Toxicol. 73 65–70

    Not in our library10.1007/s002040050588

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    Yang X. Zhang B. Molony C. Chudin E. Hao K. Zhu J. (2010 ). Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver. Genome Res. 20 1020–1036

    Not in our library10.1101/gr.103341.109

  150. 150.

    Yao S. Barlow W. E. Albain K. S. Choi J.-Y. Zhao H. Livingston R. B. (2010 ). Gene polymorphisms in cyclophosphamide metabolism pathway, treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for breast cancer. Clin. Cancer Res. 16 6169–6176

    Not in our library10.1158/1078-0432.ccr-10-0281

  151. 151.

    Yimer G. Amogne W. Habtewold A. Makonnen E. Ueda N. Suda A. (2011 ). High plasma efavirenz level and CYP2B6*6 are associated with efavirenz-based HAART-induced liver injury in the treatment of naïve HIV patients from Ethiopia: a prospective cohort study. Pharmacogenomics J. 12 499–506

    Not in our library10.1038/tpj.2011.34

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    Yuan J. Guo S. Hall D. Cammett A. M. Jayadev S. Distel M. (2011 ). Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent. AIDS 25 1271–1280

    Not in our library10.1097/qad.0b013e32834779df

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    Zanger U. M. Hofmann M. H. (2008 ). Polymorphic cytochromes P450 CYP2B6 and CYP2D6: recent advances on single nucleotide polymorphisms affecting splicing. Acta Chim. Slov. 55 38

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    Zanger U. M. Klein K. Saussele T. Blievernicht J. Hofmann M. H. Schwab M. (2007 ). Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics 8 743–759

    Not in our library10.2217/14622416.8.7.743

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    Zhang H. Amunugama H. Ney S. Cooper N. Hollenberg P. F. (2011a ). Mechanism-based inactivation of human cytochrome P450 2B6 by clopidogrel: involvement of both covalent modification of cysteinyl residue 475 and loss of heme. Mol. Pharmacol. 80 839–847

    Not in our library10.1124/mol.111.073783

  156. 156.

    Zhang H. Sridar C. Kenaan C. Amunugama H. Ballou D. P. Hollenberg P. F. (2011b ). 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. J. Pharmacol. Exp. Ther. 338 803–809

    Not in our library10.1124/jpet.111.183111

  157. 157.

    Zukunft J. Lang T. Richter T. Hirsch-Ernst K. I. Nussler A. K. Klein K. (2005 ). A natural CYP2B6 TATA box polymorphism (-82T–>C) leading to enhanced transcription and relocation of the transcriptional start site. Mol. Pharmacol. 67 1772–1782

    Not in our library10.1124/mol.104.008086

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