CYP2B6 allelic variants and non-genetic factors influence CYP2B6 enzyme function

Abstract

Human CYP2B6 enzyme although constitutes relatively low proportion (1-4%) of hepatic cytochrome P450 content, it is the major catalyst of metabolism of several clinically important drugs (efavirenz, cyclophosphamide, bupropion, methadone). High interindividual variability in CYP2B6 function, contributing to impaired drug-response and/or adverse reactions, is partly elucidated by genetic polymorphisms, whereas non-genetic factors can significantly modify the CYP2B6 phenotype. The influence of genetic and phenoconverting non-genetic factors on CYP2B6-selective activity and CYP2B6 expression was investigated in liver tissues from Caucasian subjects (N = 119). Strong association was observed between hepatic S-mephenytoin N-demethylase activity and CYP2B6 mRNA expression (P < 0.0001). In less than one third of the tissue donors, the CYP2B6 phenotype characterized by S-mephenytoin N-demethylase activity and/or CYP2B6 expression was concordant with CYP2B6 genotype, whereas in more than 35% of the subjects, an altered CYP2B6 phenotype was attributed to phenoconverting non-genetic factors (to CYP2B6-specific inhibitors and inducers, non-specific amoxicillin + clavulanic acid treatment and chronic alcohol consumption, but not to the gender). Furthermore, CYP2B6 genotype-phenotype mismatch still existed in one third of tissue donors. In conclusion, identifying potential sources of CYP2B6 variability and considering both genetic variations and non-genetic factors is a pressing requirement for appropriate elucidation of CYP2B6 genotype-phenotype mismatch.

Figure 1

Frequency distribution of hepatic CYP2B6 activities (S-mephenytoin N-demethylation) (N = 105) (A) and association between CYP2B6 activities and mRNA expression (N = 85) (B) in human tissue donors. PM poor metabolizer; IM intermediate metabolizer; EM extensive metabolizer. * Significant difference (P < 0.0001).

Figure 2

Gender-based differences in S-mephenytoin N-demethylation between various CYP2B6 metabolizer groups (A) and between CYP2B6 genotype groups (B). The inserted graph (A) displays the differences in CYP2B6 activities between men and women.

Figure 3

Hepatic CYP2B6 activity (S-mephenytoin N-demethylation) (A) and CYP2B6 expression (B) in subjects belonging to various CYP2B6 genotype groups. Non-genetic factors (CYP2B6 inducer and inhibitor therapy, amoxicillin + clavulanic acid treatment, chronic alcohol consumption) found in clinical reports of the tissue donors are indicated. The median CYP2B6 activity (dotted line) is for the cutoff value between high- and low-intermediate metabolizers. Tables provide the number of subjects in each metabolizer groups with the information of relevant non-genetic factors. PM poor metabolizer, IM intermediate metabolizer, EM extensive metabolizer, low low expression; intermediate intermediate expression; high high expression. CYP2B6 genotype groups: Poor CYP2B6*6/*6, CYP2B6*6/*9; Intermediate: CYP2B6*1/*6, CYP2B6*5/*6, CYP2B6*1/*9, CYP2B6*4/*6; Normal: CYP2B6*1/*1, CYP2B6*1/*5; Rapid: CYP2B6*1/*4, CYP2B6*1/*22, CYP2B6*4/*5. *P < 0.05.