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.

The Evaluation of CYP2D6, CYP2C9, CYP2C19, and CYP2B6 Phenoconversion in Post-Mortem Casework: The Challenge of Forensic Toxicogenetics

“…CYP2B6 represents a minority of the hepatic CYP protein content [ 42 ] but is associated with significant interindividual variations in pharmacokinetics of several drugs, including methadone and antidepressant drugs [ 53 , 54 , 55 ], which are particularly relevant in forensic toxicology. The concept of phenoconversion has been rarely applied to this enzyme but is recommended to be considered during CYP2B6 phenotype prediction [ 42 , 49 , 56 ]. Benzodiazepines such as diazepam and midazolam seem to induce transcriptional expression of the CYP2B6 gene and, in liver tissue, were associated with increased enzyme activity [ 42 ].…”

“…The concept of phenoconversion has been rarely applied to this enzyme but is recommended to be considered during CYP2B6 phenotype prediction [ 42 , 49 , 56 ]. Benzodiazepines such as diazepam and midazolam seem to induce transcriptional expression of the CYP2B6 gene and, in liver tissue, were associated with increased enzyme activity [ 42 ]. In our study, the co-consumption of diazepam, methadone, and other CYP2B6 inducers appeared to ameliorate the function of CYP2B6 predicted from genotype in 16 out of 31 cases (51.6%), while this effect was rare for other CYP450 enzymes.…”

“…Considering the high rate of subjects that tested positive for methadone and the high rate of possible modifications of its pharmacokinetics due to phenoconversion, this phenomenon seems extremely relevant and should be taken into account, particularly in the case of methadone-related intoxications. On the other hand, the challenges faced in the translation of genotype into g-phenotype and in the evaluation of the p-phenotype highlight the need for more consistent and standardized procedures in order to take into account non-genetic factors in the prediction of patients’ drug-metabolising capacity [ 42 , 45 ].…”

“…For CYP2C9 and CYP2C19 , a protocol for the adjustment of the AS value was not available, therefore the metabolic profiles have been adjusted as reported by Mostafa et al [ 36 ]. CYP2B6 adjustment of the metabolic profile in the presence of phenoconversion was performed as reported by Mangò et al [ 42 ]. In this model, CYP2B6 activity (p-phenotype) was classified in the following categories: PM, low IM-PM, high IM, high IM-extensive metaboliser (EM), NM, and EM.…”

Pharmacogenomics in Psychiatry Practice: The Value and the Challenges

“…Similarly, genetic variations in addition to the demographic parameters have been investigated to contribute to the modified CYP2B6 expression and activity [ 134 , 137 ]. Although hepatic CYP2B6 represents only a small proportion (1–4%) of the human CYP450, it is responsible for catalyzing the metabolism of many important drugs, including the atypical antidepressant bupropion [ 138 ].…”