Genetic polymorphisms in human xenobiotica metabolizing enzymes as susceptibility factors in toxic response

Abstract

Biotransformation plays an important role in the carcinogenic activity and organ specificity of environmental carcinogens. Large interindividual variation in the biotransformation has been reported, and genetic polymorphisms in some xenobiotica metabolizing enzymes can in part explain some of these differences. The concentration of the ultimate carcinogen, that will react with DNA, is determined by the rate of activation and detoxification. Individuals with a decreased rate of detoxification, i.e., lacking the glutathione S-transferase M1 gene, have a slightly higher level of bulky carcinogen-DNA adduct in some tissues, and do also have an increased level of chromosomal aberrations. In addition, the genotype may also influence the type of mutations, e.g., in tumor suppressor gene, transversion being predominant in the GSTM1 null group. People with slow N-acetyltransferase activity do generally have a higher adduct level of aromatic amines in bladder tissues. Genetic polymorphism in either CYP1A1 or glutathione S-transferase is linked to an increased risk of smoking related cancers, while N-acetyltransferase activity is related to cancers in which aromatic amines are the main risk factor. Combination of the high risk genotypes for activating and detoxification enzymes, e.g., CYP1A MspI/GSTM1 null is not only associated with an increased risk of cancer development, but also an increased level of markers of the biological active dose and early markers of effect. Additional studies on the role of genetic variants of xenobiotica metabolizing enzymes and combinations thereof at relevant low levels of exposure are important in order to establish guidance values for toxic compounds.