Novel and established CYP2A6 alleles impair in vivo nicotine metabolism in a population of Black African descent

Abstract

Cytochrome P450 2A6 (CYP2A6) is a human enzyme best known for metabolizing tobacco-related compounds, such as nicotine, cotinine (COT), and nitrosamine procarcinogens. CYP2A6 genetic variants have been associated with smoking status, cigarette consumption, and tobacco-related cancers. Our objective was to functionally characterize four nonsynonymous CYP2A6 sequence variants with respect to their haplotype, allele frequency, and association with in vivo CYP2A6 activity. In vivo, nicotine was administered orally to 281 volunteers of Black African descent. Blood samples were collected for kinetic phenotyping and CYP2A6 genotyping. In vitro, nicotine C-oxidation catalytic efficiencies of heterologously expressed variant enzymes were assessed. The four uncharacterized sequence variants were found in seven novel alleles CYP2A6(*)24A&B ; (*)25, (*)26, (*)27, and *28A&B, most were associated with impaired in vivo CYP2A6 activity. Nicotine metabolism groupings, based on the in vivo data of variant alleles, were created. Mean trans-3'-hydroxycotinine/cotinine (3HC/COT) differed (P<0.001) between normal (100%), intermediate (64%), and slow (40%) groups. Systemic exposure to nicotine following oral administration also differed (P<0.001) between normal (100%), intermediate (139%), and slow (162%) metabolism groups. In addition, alleles of individuals with unusual phenotype-genotype relationships were sequenced, resulting in the discovery of five novel uncharacterized alleles and at least one novel duplication allele. A total of 7% of this population of Black African descent had at least one of the eight novel characterized alleles and 29% had at least one previously established allele. These findings are important for increasing the accuracy of association studies between CYP2A6 genotype and behavioral, disease, or pharmacological phenotypes.

A Genome-Wide Association Study In COPD Identifies A Susceptibility Locus On Chromosome 19q13

“…synonymous SNP in CYP2A6 in our COPD cohorts (26), CYPA26 activity is affected by a number of other demonstrated functional variants-both common and rare (40)(41)(42)(43). While we failed to demonstrate an association with cigarette smoking behavior and rs7937 within our case or control groups, both the 15q25 and 19q13 loci have been associated with cotinine levels in other studies that did not find an association with cigarettes per day (44,45), suggesting that standard measures of smoking behavior are incomplete.…”

Polymorphism of Cytochrome P450 2a6 (Cyp2a6*1 and Cyp2a6*4) Among Javanese Indonesian Smoker and Non Smoker

“…Regarding the basis for the classification of the CYP2A6 genotypes into three groups, we recently analyzed that all of the smoker were classified as slow metabolizers as having CYP2A6*1/*4 genotype (Mwenifumbo et al, 2008;Schoedel et al, 2004). The results indicate that the CYP2A6 genotype does not have any notable effect on the number of smoked cigarettes among smokers.…”

“…According to the genotypes, subjects were divided into three groups: normal metabolizers, low metabolizers and poor metabolizers. In brief, normal metabolizers were defined as having allele *1/*1; slow metabolizers had allele *1/*4 which was associated with 50% of the activity of normal metabolizers; and poor metabolizers had allele *4/*4 which was associated with less than 25% of the activity of normal metabolizers (Mwenifumbo et al, 2008;Schoedel et al, 2004). The frequencies of CYP2A6 genotypes for each allele were assessed using Hardy Weinberg distribution.…”

Differential Effects of Nicotine Treatment and Ethanol Self-Administration on CYP2A6, CYP2B6 and Nicotine Pharmacokinetics in African Green Monkeys

“…This reaction is mediated primarily by CYP2A6, with some contribution from CYP2B6 (Messina et al, 1997;Yamazaki et al, 1999;Yamanaka et al, 2005). Cotinine is further metabolized to trans-3-hydroxycotinine via a reaction mediated exclusively by CYP2A6 (Nakajima et al, 1996;Mwenifumbo et al, 2008). Cigarette smoking decreases nicotine metabolism, which is in contrast to the well known effect of cigarette smoking on accelerating the metabolism of many other drugs (Zevin and Benowitz, 1999).…”