Polymorphisms of CYP2A6 and its practical consequences

CYP2A6 is an hepatic enzyme predominantly with some expression in specializ ed extrahepatic cell types. The CYP2A6 enzyme has a somewhat restricted act ive site, accepting only a few xenobiotics as substrates. Interest in CYP2A 6 has risen considerably after nicotine and some tobacco specific nitrosami nes were established as high-affinity substrates for this enzyme. Recently, the organization and structures of the CYP2A gene cluster and several poly morphic alleles of the CYP2A6 gene have been characterized. Two alleles wit h a point mutation and at least three different types of gene deletion, all leading to deficient gene function, have been found. The frequencies of th ese alleles vary considerably among different ethnic populations, the delet ion alleles being most common in Orientals (up to 20%). The frequency of po int mutations are low in all populations studied thus far (< 3%). Several c ase-control studies have addressed the relationship between CYP2A6 status a nd smoking habits as well as the role of CYP2A6 polymorphism in lung cancer risk. Studies in Japanese suggest that CYP2A6 poor metabolizer genotypes r esult in altered nicotine kinetics and may lower cigarette smoking elicited lung cancer risk, whereas similar studies in Caucasian populations have no t revealed any clear associations between valiant CYP2A6 genotypes and smok ing behaviour or lung cancer predisposition.