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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.
Highlights
Abbreviations CAR Constitutive androstane receptor Clinical Pharmacogenetics Implementation Consortium (CPIC) Clinical pharmacogenetics implementation consortium Ct Threshold cycle cytochrome P450 (CYP) Cytochrome P450 glyceraldehyde 3-phosphate dehydrogenase (GAPDH) Glyceraldehyde 3-phosphate dehydrogenase PCR Polymerase chain reaction PharmVar Pharmacogene Variation Consortium PXR Pregnane X receptor single nucleotide variations (SNVs) Single nucleotide variation
Validated TaqMan CYP2B6 genotyping assays are commercially available for g.-82 T > C, g.15631G > T and g.25505C > T polymorphisms, but not for g.18053A > G, which is present in many allelic variants including CYP2B6*4 and the most frequent and widely studied CYP2B6*6; for identification of g.18053A > G, we have developed a novel, two-step genotyping assay
Genetic polymorphisms of CYP2B6 can elucidate the substantial interindividual variability in CYP2B6 expression and activity to some extent, non-genetic factors can significantly modify the CYP2B6 phenotype predicted from genotype
Summary
Abbreviations CAR Constitutive androstane receptor CPIC Clinical pharmacogenetics implementation consortium Ct Threshold cycle CYP Cytochrome P450 GAPDH Glyceraldehyde 3-phosphate dehydrogenase PCR Polymerase chain reaction PharmVar Pharmacogene Variation Consortium PXR Pregnane X receptor SNV Single nucleotide variation. CYP2B6*4 allele contains the Lys262Arg change (rs2279343, g.18053A > G) that results in a structurally altered CYP2B6 enzyme variant and an increase in CYP2B6 enzyme activity (efavirenz hydroxylation)[9,12,13,14]. The g.15631G > T (rs3745274, Gln172His) nucleotide substitution was detected in CYP2B6*9 allele resulting in decreased enzyme activities (both bupropion and efavirenz hydroxylation) to CYP2B6*620; information about the clinical significance of CYP2B6*9 is hardly available because of its low prevalence in all populations. The g.25505C > T (rs3211371, Arg487Cys) nucleotide change in CYP2B6*5 allele-variant has been reported to display mild or negligible effect on CYP2B6 catalytic activity, it seemed to influence the CYP2B6 protein e xpression[15,16,17,21,22]. We attempted to identify non-genetic factors including demographic parameters and co-medication that can modify CYP2B6 phenotype predicted from genotype
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