Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance

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From: Pharmacogenomics(Vol. 8, Issue 7)
Publisher: Future Medicine Ltd.
Document Type: Clinical report
Length: 11,043 words

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Author(s): Ulrich M Zanger [[dagger]] 1 2 , Kathrin Klein 1 2 , Tanja Saussele 1 2 , Julia Blievernicht 1 2 , Marco H Hofmann 1 2 , Matthias Schwab 1 2

Keywords:

AIDS; bupropion; cyclophosphamide; cytochrome P450; efavirenz; HIV; non-nucleoside reverse transcriptase inhibitors; pharmacogenetics; pharmacogenomics; SNP

Approximately 12 cytochrome P450 (CYP) isozymes of families CYP1, CYP2 and CYP3 are collectively responsible for most Phase I biotransformations of drugs and other xenobiotics in human liver [1] . Expression and function of these isozymes are extremely variable both inter- and intra-individually, which represents a major determinant for unpredictable drug and drug-metabolite plasma concentrations and, ultimately, for unforeseen drug responses. Genetic polymorphisms in CYP and other drug-metabolism enzyme and transporter genes are an important source of variation, but induction/repression or inhibition by drugs and other xeno- or endo-biotics, biological or physiological conditions, including sex, age, disease and many other confounding factors, often limit their penetrance [2-4] .

CYP2B6 belongs to the less well-characterized human CYP isoforms [5] . The initial lack of knowledge regarding selective substrates and inhibitors impeded its phenotypic characterization and identification of pharmacogenetic effects. As an orthologue to the rodent phenobarbital-inducible CYP2B genes, human CYP2B6 is strongly inducible by numerous drugs and other xenobiotics [6] , and this certainly masks pharmacogenetic phenotypes to some extent. Thus, compared with the well-studied model polymorphisms of CYP2D6 and CYP2C19 , which both originated from clinical observations [7] , polymorphic CYP2B6 is rather an instructive example for the successful application of 'reverse pharmacogenetics'. With 28 alleles currently defined, and over 100 described SNPs, CYP2B6 appears to be one of the most polymorphic CYP genes in humans (The Human Cytochrome P450 [CYP ] Allele Nomenclature Committee [201] ). These sequence variations include nonsynonymous, silent, promoter and intronic changes, many of them showing extensive linkage disequilibrium (LD) giving rise to distinct haplotypes with a wide spectrum of functional consequences, including null alleles, partially reduced function/expression alleles and alleles with increased activity. Many of these polymorphisms are rare, but others are common, with allele frequencies of 5% and up to over 50%, respectively, and with marked interethnic differences [8] . The possible significance of CYP2B6 pharmacogenetics for clinical drug treatment is just emerging as the field is in its infancy. Consistent pharmacokinetic effects have so far been demonstrated for the anti-HIV drug efavirenz [9] , and promising findings have been reported for a few other drugs. This review will discuss the molecular basis of CYP2B6 polymorphism, its interethnic variations, examples of clinical applications and possible future developments.

Molecular genetics & regulation

The human CYP2B genes were originally identified by their high sequence similarity to the rat phenobarbital-inducible CYP2B1/2 genes [10,11] . The multiple variant transcripts that were initially observed made it difficult to understand the structure of the locus and to determine the number of distinct CYP2B genes. Hoffman and colleagues presented a detailed map of the human 350 kb CYP2ABFGST gene cluster, which contains genes and pseudogenes of the CYP2A , 2B , 2F , 2G , 2S and 2T subfamilies [12,13] . In contrast to the considerably larger number of expressed functional CYP2B genes in...

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Gale Document Number: GALE|A225110118