Elsevier

Advanced Drug Delivery Reviews

Volume 54, Issue 10, 18 November 2002, Pages 1245-1256
Advanced Drug Delivery Reviews

CYP2A6 genetic variation and potential consequences

https://doi.org/10.1016/S0169-409X(02)00065-0Get rights and content

Abstract

Human cytochrome P450 2A6 (CYP2A6) has been shown to have large interindividual and interethnic variability in levels of expression and activity. This is thought to be largely due to genetic polymorphisms. In recent years, 13 genetic variants (CYP2A6*1*11 and the gene duplication, *1×2) of CYP2A6 have been identified and a number of these have been shown to result in altered CYP2A6 enzyme activity. For example, there are alleles which result in variants that are in inactive (e.g. due to a gene deletion), have decreased activity (e.g. altered enzyme structure or transcriptional activity) or have increased activity (e.g. due to gene duplications). The resulting interindividual variation in metabolic activity may affect the metabolism of CYP2A6 substrates including nicotine, cotinine (the major metabolite of nicotine), several tobacco-specific procarcinogens, coumarin and many toxins. The frequencies of the CYP2A6 alleles vary considerably among different ethnic populations, which may partially explain the interethnic variability found in CYP2A6-related metabolic activity (e.g. nicotine metabolism), behaviors (i.e. smoking) and disease (i.e. lung cancer). Investigations of the genetic variation of CYP2A6 and its resulting effects on metabolism and health consequences are still fairly early; this review summarizes what is presently known about CYP2A6, its genetic variants and their clinical consequences.

Introduction

Cytochromes P450 (CYPs) are a superfamily of enzymes involved in the metabolism of endogenous and exogenous compounds. A great deal of interindividual and interethnic variability in the activity and levels of these enzymes exist which may lead to differences in the effects and toxicities of many drugs (clinical and recreational) and environmental compounds (reviewed in Ref. [1]). The causes of this variability include both genetic and environmental factors. It has been estimated that ∼20–40% of the interindividual variability in drug metabolism and drug response can be attributed to the existence of polymorphisms in CYP [1]. Many allelic variants of CYP2A6, which is a member of the CYP2A subfamily, have been identified over the past 5 years. CYP2A6 participates in the metabolism of several compounds including drugs, toxins and procarcinogens whose blood levels, actions and duration of effects may be altered by polymorphisms in this gene. This review will summarize the current knowledge on CYP2A6, its genetic variants and their potential for clinical consequences.

Section snippets

The cytochrome P450 superfamily

CYPs are heme-containing enzymes which catalyse the metabolism of a wide variety of compounds including environmental pollutants and dietary chemicals. CYP genes are designated by a family number, a subfamily letter then a number and an asterisk followed by a number(s) for each allelic variant (i.e. CYP2A6*2) [2]. A CYP allele database has been constructed and is available online [3]. CYPs are categorised into their families and subfamilies based on their sequence similarities. Those with amino

Substrates

The CYP2A6 enzyme, which is primarily expressed in the liver, was first recognized for its involvement in the metabolism of coumarin [5], a naturally occurring plant compound. CYP2A6 is selective for coumarin 7-hydroxylation making coumarin a selective in vitro and in vivo probe for measuring CYP2A6 activity [6]. In recent years, the role of CYP2A6 in nicotine metabolism has become of interest. On average, 80% of nicotine is inactivated to cotinine in vivo by C-oxidation [7]. CYP2A6 is the

Structural organization of the CYP2A6 gene

The human CYP2A6 gene was cloned and sequenced in 1990 [18], [19]. Its gene locus spans a region of 6 kbp, contains nine exons and has been physically mapped to the long arm of chromosome 19 between 19q12 and 19q13.2 [20], [21]. It is located within a 350-kbp gene cluster containing the CYP2A7 and CYP2A13 genes which show high sequence homology to the CYP2A6 gene [12], [20], [21], [22]. CYP2A13 is mostly expressed in the nasal mucosa, lung and trachea. It has been shown to be only one-tenth as

CYP2A6 and pharmacogenetics

In the past several years, the role of CYP2A6 and the consequences of its genetic variants have become the focus of numerous studies. To date, 13 allelic variants of the CYP2A6 gene have been discovered (*1*11 and the gene duplication). Several of these variants result in altered enzyme activity that may consequently affect the metabolism of CYP2A6 substrates including clinically and non-clinically used drugs, toxins and procarcinogens; understanding the genetic variation and clinical

CYP2A6 genetic variation and potential consequences

In the past several decades, techniques have evolved which allow us to study the role of genetic factors in human diseases and disorders. As mentioned, CYP2A6 is involved in the metabolism of nicotine, some procarcinogens and several toxins. Variation in this gene leads to altered enzyme activity and consequently to changes in the metabolism of these compounds. This section summarizes how the CYP2A6 variants may affect smoking, cancer, as well as the treatment of cigarette smoking and other

Concluding remarks and future directions

Large advancements in our understanding of CYP2A6 have occurred in the past several years, however it is obvious that major scientific gaps still exist. Further research concentrating on the CYP2A6 gene, its variants and their clinical consequences will improve our understanding of the role that CYP2A6 genetic variation plays in interindividual differences in metabolism and clarify some of the incomplete and/or conflicting data. We believe that this will also provide us with new options for

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