Variation in CYP2A6 Activity and Personalized Medicine

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.

Comprehensive overview of the pharmacogenetic diversity in Ashkenazi Jews

“…Notably, genetic variability differed substantially across genes (figure 1). CYP2A6 is the principal enzyme involved in nicotine and tobacco-specific nitrosamine metabolism, and decreased CYP2A6 activity is associated with reduced nicotine dependence and lung cancer risk 25. In CYP2A6 , 30.4% of all alleles harboured characterised variant haplotypes, of which *35 , a missense mutation in exon 9, was the most prevalent (MAF=12%; table 1).…”

CYP2B6 Genotype‐Dependent Inhibition of CYP1A2 and Induction of CYP2A6 by the Antiretroviral Drug Efavirenz in Healthy Volunteers

“…This together with the fact that CYP2A6 is also transcriptionally regulated via PXR and CAR may explain our observed increase in CYP2A6 activity following efavirenz treatment. CYP2A6 catalyzes, fully or partially, the metabolism of several clinically used drugs (e.g., letrozole, metronidazole, efavirenz, and tegafur) and, based on our findings, it is anticipated that efavirenz would alter the disposition of these drugs. CYP2A6 is also the main metabolic pathway for nicotine elimination and contributes to the biotransformation of several nicotine‐derived carcinogens (N′‐nitrosonornicotine and 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone .…”

“…CYP2A6 catalyzes, fully or partially, the metabolism of several clinically used drugs (e.g., letrozole, metronidazole, efavirenz, and tegafur) and, based on our findings, it is anticipated that efavirenz would alter the disposition of these drugs. CYP2A6 is also the main metabolic pathway for nicotine elimination and contributes to the biotransformation of several nicotine‐derived carcinogens (N′‐nitrosonornicotine and 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone . Hepatic CYP2A6 activity has been associated with the number of cigarettes smoked per day, smoking topography (puff volume, duration, and velocity), and smoking cessation .…”

“…CYP2A6 is also the main metabolic pathway for nicotine elimination and contributes to the biotransformation of several nicotine‐derived carcinogens (N′‐nitrosonornicotine and 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone . Hepatic CYP2A6 activity has been associated with the number of cigarettes smoked per day, smoking topography (puff volume, duration, and velocity), and smoking cessation . Thus, it is conceivable that cigarette smokers would be at increased risk for tobacco‐related illnesses when coprescribed efavirenz‐based HIV therapy.…”

Comprehensive Analysis of the Expression and Prognosis of 12 Cytochrome P450s in Human Hepatocellular Carcinoma from the Perspective of Network Pharmacology

“…CYP2A6 exerts a key effect on the outcome of resected gastric cancer [37] and HCC [38] via 5uorouracil metabolism. As the metabolic-activating enzyme of most tobacco carcinogens, CYP2A6 is notably involved with the risk of lung cancer [39] and is a crucial clinical consideration for personalized medicine [40]. The expression levels of CYP2A6 and CYP2A7 are lower in patients with hepatitis B virus and HCV than those in healthy people [41].…”