Genetic polymorphisms in the cytochrome P450 2A6 (CYP2A6) gene: Implications for interindividual differences in nicotine metabolism

During the last couple of years, cytochrome P450 2A6 (CYP2A6; coumarin 7-hy droxylase) has received a lot of attention because it has been shown that i t is the principle human nicotine C-oxidase. This enzyme also activates a n umber of structurally unrelated precarcinogens including many nitrosamines and aflatoxin B1, and metabolizes certain clinically used drugs. There is a pronounced interindividual and interethnic variability in CYP2A6 levels an d activity, and much of this can be attributed to polymorphisms in the CYP2 A6 gene, where a few inactivating mutations as well as gene deletions have been described. The frequency of the inactive alleles is low in European po pulations and very few poor metabolizers for the probe drug coumarin have b een described in these populations. In contrast, a relatively high allele f requency (15-20%) of the CYP2A6 gene deletion has been found in Asians, res ulting in a generally reduced activity in these populations. Because of the importance of CYP2A6 in nicotine metabolism, it has been suggested that th e CYP2A6 genotype influences the interindividual differences in smoking beh avior as well as lung cancer susceptibility. Several case-control studies h ave been conducted in this area, but these have yielded conflicting results . The recent progress in the field of CYP2A6 genetics and the development o f more specific genotyping methods will facilitate molecular epidemiologica l studies aimed at clarifying these important issues.