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 enzymes, especially those involved in the biotransformation of aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs). Metabolic activation generally involves an initial cytochrome P450-dependent oxidation to form N-hydroxy, phenol, or dihydrodiol intermediates that undergo further conjugation or oxidation to form DNA adducts. The acetyltransferases, NAT1 and NAT2, can participate in these pathways by catalyzing detoxification (by AA N-acetylation) or further activation (by N-OH-AA O-acetylation) reactions. NAT2 polymorphisms, which are due to point 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 been associated with increased bladder cancer risk. Moreover, we have found that the bladder NAT1*10 genotype and phenotype are correlated with significantly higher levels of putative AA-DNA adducts in human bladder as measured by 32P-postlabelling. Preliminary data have also suggested that putative PAH-DNA adducts in human bladder are correlated with a polymorphism in the total metabolism of benzo[a]pyrene (BP) by bladder microsomes and especially with the formation of BP-7,8-diol. Since each of these correlations was observed without adjusting for carcinogen intake, it would appear that, with ubiquitous human exposure to AAs and PAHs, the expression of carcinogen-metabolizing enzymes may be a more critical determinant of carcinogen-DNA adduct formation and of individual cancer susceptibility.
Kadlubar
F F
FF
Division of Molecular Epidemiology (HFT-100), National Center for Toxicological Research (NCTR), Jefferson, AR 72079, USA.
Badawi
A F
AF
D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D002273:Carcinogens / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism*; D006801:Humans; D011110:Polymorphism, Genetic; D001743:Urinary Bladder / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism
D002273:Carcinogens; D018736:DNA Adducts; D001191:Arylamine N-Acetyltransferase