POLYMORPHISMS OF CYP1A1 AND GSTM1 INFLUENCE THE IN-VIVO FUNCTION OF CYP1A2

Differences in human cancer susceptibility have been attributed to pol ymorphisms of carcinogen metabolizing enzymes. Our efforts have focuse d on the systems responsible for metabolism of aromatic and heterocycl ic amines found in cigarette smoke and in cooked foods. Cytochrome P45 01A2 (CYP1A2), which catalyzes aromatic and heterocyclic amine N-oxida tion, has been implicated as a risk factor in both urinary bladder and colorectal cancer. In the present study we used the results of caffei ne phenotyping experiments to measure the effects of cigarette smoke a nd compounds present in meat cooked at high temperature on CYP1A2 acti vity. Subjects in the smoking cessation study had mean CYP1A2 activity of 17.8 (expressed as the urinary molar ratio of [17X + 17U]/137X) wh ile smoking; however, this activity decreased to 10.9 three weeks afte r cessation of smoking. Subjects in the cooked meat feeding study had mean CYP1A2 activity of 9.01 after 1 week of consuming meat cooked at low temperature, but this value increased to 12.7 after I week of cons uming meat cooked at high temperature. Because no association has been identified between differences in CYP1A2 activity and variations in t he CYP1A2 structural gene, we sought to determine whether the activiti es of other carcinogen metabolizing enzymes are involved in the regula tion of CYP1A2 activity. CYP1A2 activity was higher in individuals who express the GSTM1 null allele compared to those expressing the GSTM1 A,B allele, 10.2 vs. 8.5 for unexposed conditions and 15.0 vs. 12.3 fo r exposed conditions. CYP1A1 genotyping demonstrated that individuals possessing the Ile/Ile CYP1A1 genotype had greater mean CYP1A2 activit y than those who had the heterozygous Ile/Val allelic variant of the C YP1A1 gene. However, upon exposure to cigarette smoke or high-temperat ure cooked meat, individuals possessing the heterozygous form of the C YP1A1 gene had significantly increased CYP1A2 activity (18.1) compared to those with the more common Ile/Ile CYP1A1 genotype (13.3). These r esults indicate that CYP1A2, CYP1A1, and GSTM1 gene-gene interactions could be important confounders in the interpretation of molecular epid emiology studies.