Variation in CYP2A6 Activity and Personalized Medicine

Julie-Anne Tanner, Rachel F Tyndale, Julie-Anne Tanner, Rachel F Tyndale

Abstract

The cytochrome P450 2A6 (CYP2A6) enzyme metabolizes several clinically relevant substrates, including nicotine-the primary psychoactive component in cigarette smoke. The gene that encodes the CYP2A6 enzyme is highly polymorphic, resulting in extensive interindividual variation in CYP2A6 enzyme activity and the rate of metabolism of nicotine and other CYP2A6 substrates including cotinine, tegafur, letrozole, efavirenz, valproic acid, pilocarpine, artemisinin, artesunate, SM-12502, caffeine, and tyrosol. CYP2A6 expression and activity are also impacted by non-genetic factors, including induction or inhibition by pharmacological, endogenous, and dietary substances, as well as age-related changes, or interactions with other hepatic enzymes, co-enzymes, and co-factors. As variation in CYP2A6 activity is associated with smoking behavior, smoking cessation, tobacco-related lung cancer risk, and with altered metabolism and resulting clinical responses for several therapeutics, CYP2A6 expression and enzyme activity is an important clinical consideration. This review will discuss sources of variation in CYP2A6 enzyme activity, with a focus on the impact of CYP2A6 genetic variation on metabolism of the CYP2A6 substrates.

Keywords: CYP2A6; SNP; drug metabolism; genetic variation; inducer; inhibitor; nicotine; pharmacogenetics; pharmacogenomics; smoking.

Conflict of interest statement

Tyndale has consulted for Apotex and Quinn Emanuel on unrelated topics. The remaining author declares no conflicts of interest. This work was supported by a Canada Research Chair in Pharmacogenomics (R.F.T.), CIHR FDN-154294, and the Campbell Family Mental Health Research Institute of CAMH.

Figures

Figure 1
Figure 1
The major pathways of nicotine metabolism and clearance. The bolded arrow represents the predominant pathway of nicotine metabolism (CYP2A6 is responsible for 90% of nicotine’s metabolism to cotinine). Adapted from Hukkanen et al., 2005 [103] and Tanner et al., 2015 [41].

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