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Structure, Function, Regulation and Polymorphism of Human Cytochrome P450 2A6

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Abstract:

The CYP2A6 gene spans a region of approximately 6 kb pairs consisting of 9 exons and has been mapped to the long arm of chromosome 19 (between 19q12 and 19q13.2). The CYP2A6 protein has 494 amino acids and is an important hepatic Phase I enzyme that metabolizes ∼3% of therapeutic drugs (n > 30; e.g. valproic acid, pilocarpine, tegafur, fadrozole, ifosfamide, cyclophosphamide, nicotine, tamoxifen, promazine, propofol, and cisapride), environmental toxicants (e.g. gasoline additives), and many procarcinogens such as nitrosamines and aflatoxin B1. This enzyme also participates in the biotransformation of several endogenous compounds such as retinoid acids and steroids. Because CYP2A6 is responsible for 70-80% of the initial metabolism of nicotine, CYP2A6 has been proposed to be a novel target for smoking cessation. Site-directed mutagenesis and homology modeling studies have identified a number of amino acids (e.g. F300, A301, S208, S369, and L370) that play a role in substrate recognition and binding. CYP2A6 shows a crystal structure with a compact, hydrophobic active site with Asn297 serving as one hydrogen bond donor and orienting substrates for regio-selective oxidation. CYP2A6 contains the second smallest active site cavity among the human CYPs with known structures. The regulation mechanism of CYP2A6 expression is not fully understood, but available data suggest that several nuclear receptors including constitutive androstane receptor, pregnane X receptor and glucocorticoid receptor are involved in its regulation. Pilocarpine and tranylcypromine are commonly used as selective competitive inhibitors of CYP2A6. Selegiline, methoxsalen, (R)-(+) menthofuran and decursinol angelate are mechanism-based inhibitors of CYP2A6. Both in vitro and in vivo studies have demonstrated a wide (20- to >100-fold) interindividual variation in CYP2A6 expression and activity, which is due primarily to genetic polymorphisms in the CYP2A6 gene, but CYP2A6 activity is also modified by certain drugs and pathological and environmental factors. To date, more than 36 variant alleles (*1B through *37) of the CYP2A6 gene have been identified. There have been 278 SNPs found in the CYP2A6 upstream sequence, 8 introns and 9 exons in NCBI dbSNP. Polymorphism of CYP2A6 has been associated with smoking behavior, drug clearance and lung cancer risk. Further studies are warranted to explore the role of CYP2A6 in clinical practice, drug development and toxicology.





Keywords: CYP2A6; inhibitor; nicotine; nuclear receptor; polymorphism

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/138920009789895507

Publication date: September 1, 2009

More about this publication?
  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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