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-hydroxylase) has received a lot of attention because it has been shown that it is the principle human nicotine C-oxidase. This enzyme also activates a number 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 and activity, and much of this can be attributed to polymorphisms in the CYP2A6 gene, where a few inactivating mutations as well as gene deletions have been described. The frequency of the inactive alleles is low in European populations and very few poor metabolizers for the probe drug coumarin have been described in these populations. In contrast, a relatively high allele frequency (15-20%) of the CYP2A6 gene deletion has been found in Asians, resulting in a generally reduced activity in these populations. Because of the importance of CYP2A6 in nicotine metabolism, it has been suggested that the CYP2A6 genotype influences the interindividual differences in smoking behavior as well as lung cancer susceptibility. Several case-control studies have been conducted in this area, but these have yielded conflicting results. The recent progress in the field of CYP2A6 genetics and the development of more specific genotyping methods will facilitate molecular epidemiological studies aimed at clarifying these important issues.