CYP2B6: new insights into a historically overlooked cytochrome P450 isozyme

Abstract

Human CYP2B6 has been thought to account for a minor portion (<1%) of total hepatic cytochrome P450 (CYP) content and to have a minor function in human drug metabolism. Recent studies, however, indicate that the average relative contribution of CYP2B6 to total hepatic CYP content ranges from 2% to 10%. An increased interest in CYP2B6 research has been stimulated by the identification of an ever-increasing substrate list for this enzyme, polymorphic and ethnic variations in expression levels, and evidence for cross-regulation with CYP3A4, UGT1A1 and several hepatic drug transporters by the nuclear receptors pregnane X receptor and constitutive androstane receptor. Moreover, 20- to 250-fold interindividual variation in CYP2B6 expression has been demonstrated, presumably due to transcriptional regulation and polymorphisms. These individual differences may result in variable systemic exposure to drugs metabolized by CYP2B6, including the antineoplastics cyclophosphamide and ifosfamide, the antiretrovirals nevirapine and efavirenz, the anesthetics propofol and ketamine, the synthetic opioid methadone, and the anti-Parkinsonian selegiline. The potential clinical significance of CYP2B6 further enforces the need for a comprehensive review of this xenobiotic metabolizing enzyme. This communication summarizes recent advances in our understanding of this traditionally neglected enzyme and provides an overall picture of CYP2B6 with respect to expression, localization, substrate-specificity, inhibition, regulation, polymorphisms and clinical significance. Emphasis is given to nuclear receptor mediated transcriptional regulation, genetic polymorphisms, and their clinical significance.

Fig. 1

Pie charts for hepatic CYP expression and their contribution to metabolism of clinically-used drugs. (A) Relative hepatic expression of CYP content. (B) Contribution to drug metabolism. Due to substrate overlap among CYP isozymes, the total of contributions is moderately >100%.

Fig. 2

Human CAR preferentially binds DR4 containing CYP2B6-PBREM over ER6 containing CYP3A4-PXRE. ChIP assay was performed in a V5-hCAR stable HepG2 cell line (Yh-18)[160]. (A) PCR amplification efficiency was tested by using in put DNA. (B) DNA extracted from V5-antibody or anti-mouse IgG precipitated chromatin was analyzed by PCR. DEC2 was used as a non hCAR target gene control as described previously [161].

Fig. 3

Human CAR translocates in CAR -/- mouse liver in response to CLZ. A fluorescent-hCAR (EYFP-hCAR) was introduced into CAR -/- mice through tail vein injection, and mice was then treated with CLZ (90 mg/kg body weight), or DMSO, intraperitoneally. Animals were sacrificed 7 h later, and frozen liver sections were prepared for analysis by confocal microscopy as described previously [99].