Hepatic CYP2B6 is altered by genetic, physiologic, and environmental factors but plays little role in nicotine metabolism

Abstract

1. Human cytochrome P4502B6 (CYP2B6) is predominantly expressed in the liver and it plays a major role in the metabolism of several therapeutically important drugs and environmental toxicants.

2. The objective was twofold: (1) to determine the role of genetic, physiological, and environmental factors in predicting hepatic CYP2B6 protein expression; and (2) to investigate the role of CYP2B6 in nicotine C-oxidation.

3. Human livers (n = 40) were assessed for CYP2B6 protein and genotype.

4. Linear regression analyses indicated that CYP2B6 genotype (10%), gender (14%), and exposure to inducers (21%), but not age, were predictors of CYP2B6 protein amounts. Livers with at least one CYP2B6*5 or *6 allele were associated with lower CYP2B6. Female livers and livers exposed to inducers (phenobarbital and/or dexamethasone) were associated with higher CYP2B6.

5. A weak correlation between CYP2B6 and nicotine C-oxidation activity was observed, which was abrogated when controlling for CYP2A6 protein levels. CYP2B6*6 was not associated with different nicotine kinetics.

6. In summary, CYP2B6 protein expression was associated with genotype, gender, and exposure to inducers, but not with nicotine C-oxidation activity.

Keywords::

• CYP2B6
• CYP2A6
• nicotine
• pharmacogenetics
• age
• gender

Acknowledgements

The authors thank Ewa B. Hoffmann and William Kim for the original development of the CYP2B6*5 assay. The authors also thank Fariba Baghai Wadji, Sharon Miksys, Andy Z. X. Zhu, and Amandeep Mann for their technical assistance.

Declaration of interest

This work was supported by the Centre for Addiction and Mental Health and Canadian Institutes for Health Research (CIHR) MOP86471. N. K. received funding from the CIHR-Strategic Training Program in Tobacco use in Special Population (TUSP) and an Ontario Graduate Scholarship program (OGS). R. F. T. holds a Canada Research Chair in Pharmacogenetics. Possible conflicts of interest (including financial and other relationships) for each author include the following. Dr R. F. Tyndale has shares in Nicogen Research, Inc., a company focused on novel smoking cessation treatment approaches. None of the data contained in this manuscript alters or improves any commercial aspect of Nicogen and no Nicogen funds were used in this work.