Genetic polymorphisms in xenobiotic metabolizing enzymes as a determinant of susceptibility to environmental mutagens and carcinogens in humans

Xenobiotic metabolizing enzymes are known to play a role in the metabolic activation of environmental mutagens and carcinogens to exert their carcinogenic effects as well as detoxification by increasing their hydrophilicity. These enzymes include cytochrome P450s, glutathione S-transferases (GSTs), acetyltransferases (NATs) and sulfotransferases. Genetic polymorphisms in many of these enzymes, such as CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP2E1, NAT1, NAT2, GSTM1, GSTP1 and GSTT1, have been shown to occur, which result in the altered expression of enzymatic activities. This suggests that the genetic polymorphisms may affect the individual susceptibility to environmental carcinogens and thus play a role in human carcinogenesis. Recently, the mutations that confer those polymorphisms of xenobiotic metabolizing enzymes have been identified and genotyping methods for the genetic polymorphisms have been developed. Specific phenotypes and genotypes for CYP1A1, CYP2D6, CYP2E1, NAT1, NAT2, GSTM1 and GSTP1 have been associated with susceptibility to malignant diseases including lung, bladder and colon cancers, although the association was not confirmed in some studies. A number of factors such as degree of exposure to environmental carcinogens and the role of xenobiotic metabolizing enzymes in human carcinogenesis should carefully be evaluated in understanding genetic susceptibility.