PharmVar GeneFocus: CYP2B6

Abstract

The Pharmacogene Variation Consortium (PharmVar) catalogs star (*) allele nomenclature for the polymorphic human CYP2B6 gene. Genetic variation within the CYP2B6 gene locus impacts the metabolism or bioactivation of clinically important drugs. Of particular importance are efficacy and safety concerns regarding: efavirenz, which is used for the treatment of HIV type‐1 infection; methadone, a mainstay in the treatment of opioid use disorder and as an analgesic; ketamine, used as an antidepressant and analgesic; and bupropion, which is prescribed to treat depression and for smoking cessation. This GeneFocus provides a comprehensive overview and summary of CYP2B6 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

CYP2B6 Functional Variability in Drug Metabolism and Exposure Across Populations—Implication for Drug Safety, Dosing, and Individualized Therapy

“…Poor metabolizers are likely to experience more ADRs (active compounds) or treatment failure (prodrugs) than intermediate or normal metabolizers. According to literature, CYP2B6 * 6, which is a haplotype of two variants, CYP2B6 * 4 and CYP2B6 * 9, is the most studied allele (Li et al, 2012 ; Desta et al, 2021 ). Due to the increasing knowledge on the role of CYP2B6 enzyme in drug metabolism, there is the need to evaluate other CYP2B6 variants on substrate metabolism in various populations or ethnicity.…”

“…According to the information gathered, some studies considered the G516T ( * 4) variant as CYP2B6 * 6 allele, to maintain a common style of variant nomenclature in articles. Researchers can make use of the publicly available pharmacogene variation (PharmVar) website, which clearly defines each haplotype or alleles (Desta et al, 2021 ). CYP2B6 loss of function alleles (poor metabolizer genotypes), which lead to an increase in individual active drug exposure and toxicity are frequent in some populations leading to high risk of ADRs in these populations.…”

“…These variants are referred as star alleles on the Pharmacogene Variation website with designated clinical function as normal, decrease, increase, no or uncertain function (Thorn et al, 2010 ). Compared to other well-studied phase I enzymes such as CYP2D6, CYP2C19 and CYP2C9, CYP2B6 at first had been thought to play a minor role in human drug metabolism (Desta et al, 2021 ). However, with the increase in techniques to evaluate its regulation, relative hepatic expression and function, it became evident that CYP2B6 constitutes up to 10% of the functional CYP enzymes in the liver.…”

Computational Tools to Assess the Functional Consequences of Rare and Noncoding Pharmacogenetic Variability

“…A recent study analyzed 14,891 genomes across five different human populations and identified 433,371 SVs, which substantially surpassed previous estimates, suggesting that structural variation constitutes a common phenomenon with important impacts on a plethora of traits 89 . Structural variation is highly relevant in multiple pharmacogenes, such as CYP2B6 and CYP2D6 , where deletions, duplications, and other complex rearrangements can result in altered gene copy numbers, which in turn can be functional or inactive 90,91 …”

Pharmacogene Variation Consortium: A Global Resource and Repository for Pharmacogene Variation

“…Clinically important pharmacogenes for which Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are available such as CYP2B6, CYP2C9, CYP2C19, CYP2D6 , and CYP3A5 have extensively been curated by PharmVar gene experts ( Table ). These efforts are described in detail in the PharmVar GeneFocus series of review articles which have been published for CYP2B6 , 1 CYP2C9 , 2 CYP2C19 , 3 and CYP2D6 4 . These reviews provide a plethora of other information that not only complements CPIC guidelines but also serves as a guide to the gene’s nomenclature, to information displayed on the PharmVar gene page, and to information regarding the characterization of novel alleles, and more, which is critical information whether one is a clinician or basic scientist.…”