GENETIC SUSCEPTIBILITY AND CARCINOGEN-DNA ADDUCT FORMATION IN HUMAN URINARY-BLADDER CARCINOGENESIS

Differences in human urinary bladder cancer susceptibility have often been attributed to genetic polymorphisms in carcinogen-metabolizing en zymes, especially those involved in the biotransformation of aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs). Metabolic ac tivation generally involves an initial cytochrome P450-dependent oxida tion to form N-hydroxy, phenol, or dihydrodiol intermediates that unde rgo further conjugation or oxidation to form DNA adducts. The acetyltr ansferases, NAT1 and NAT2, can participate in these pathways by cataly zing detoxification (by AA N-acetylation) or further activation (by N- OH-AA O-acetylation) reactions. NAT2 polymorphisms, which are due to p oint mutations in the structural gene, have long been associated with higher risk for bladder cancer. In collaborative studies, we now have found that NAT1 is also expressed polymorphically in human bladder due to mutations in the NAT1 polyadenylation signal, which has recently b een associated with increased bladder cancer risk. Moreover, we have f ound that the bladder NAT110 genotype and phenotype are correlated wi th significantly higher levels of putative AA-DNA adducts in human bla dder as measured by P-32-postlabelling. Preliminary data have also sug gested that putative PAH-DNA adducts in human bladder are correlated w ith a polymorphism in the total metabolism of benzo[a]pyrene (BP) by b ladder microsomes and especially with the formation of BP-7,8-diol. Si nce each of these correlations was observed without adjusting for carc inogen intake, it would appear that, with ubiquitous human exposure to AAs and PAHs, the expression of carcinogen-metabolizing enzymes may b e a more critical determinant of carcinogen-DNA adduct formation and o f individual cancer susceptibility.