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.
Highlights
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
We will highlight the clinical relevance of variable cytochrome P450 2A6 (CYP2A6) enzyme activity, as CYP2A6 variation is associated with smoking behavior, smoking cessation, tobacco-related lung cancer risk, and with altered metabolism and resulting clinical responses for several therapeutics
CYP2A6 was not included in the array of cytochrome P450 enzymes (CYPs) that were investigated in this study, AKR1D1 and CYP2A6 mRNA, protein, and enzyme activity were moderately positively correlated, and AKR1D1 mRNA expression accounted for a significant proportion (16%) of the variation in CYP2A6 mRNA levels in a human liver bank [4]
Summary
The human cytochrome P450 2A6 (CYP2A6) enzyme, primarily expressed in the liver, metabolizes several clinically relevant substrates [1,2]. Variation in CYP2A6 activity is an important clinical consideration as this enzyme is involved in the metabolism or bioactivation of clinical therapeutics, carcinogens, and dietary substances, including nicotine, tegafur, letrozole, efavirenz, N-nitrosonornicotine (NNN), 4-(methylnitrosamino)1-(3-pyridyl)-1-butanone (NNK), and caffeine, among others [10,11,12,13,14,15,16]. Med. 2017, 7, 18 the ratio of nicotine’s metabolites 3HC/COT (referred to as the nicotine metabolite ratio, NMR), is stable in current smokers and functions as a surrogate measure of the rate of nicotine metabolism and an in vivo biomarker of CYP2A6 enzyme activity [18]. We will highlight the clinical relevance of variable CYP2A6 enzyme activity, as CYP2A6 variation is associated with smoking behavior, smoking cessation, tobacco-related lung cancer risk, and with altered metabolism and resulting clinical responses for several therapeutics
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