In l996, there were an estimated 50,500 new cases and 11,200 deaths due to bladder cancer in the US. The high incidence of bladder cancer among smokers and workers in dye, rubber, and chemical industries is associated with their exposure to aromatic amines. Benzidine is an aromatic amine associated with the development of bladder cancer in occupationally exposed humans. Workers exposed to benzidine contain N'-(3'-monophospho-deoxyguanosin-8-yl)-N- acetylbenzidine (dGp-ABZ) in their exfoliated bladder cells. dOp-ABZ causes genotoxic lesions, resulting in mutations in various bacterial and mammalian test systems in vitro and in oncogenes of tumors. dGp-ABZ is considered an endproduct of the initiation process. The principal investigator proposes to elucidate the pathways involved in benzidine metabolism and dGp-ABZ formation in humans exposed to benzidine. His model (Figure 1) proposes that dGp-ABZ formation is a complex phenomena influenced by hepatic metabolism, excretion and accumulation of metabolites in urine (Specific Aim 3); epithelial cell metabolism (Specific Aim 2); and finally dGp-ABZ formation (Specific Aim 1). To avoid problems with extrapolation of interspecies data, results with human tissue will be emphasized.
The specific aims are: 1. Determine mechanisms for formation of dGp-ABZ. Adduct formation by peroxidation, O-acetylation, and N,O-transacetylation will be assessed along with DNA sequence specificity. 2. Investigate urothelial cell metabolism of benzidine metabolites. Incubations with primary cultures of human urothelial cells will indicate He probable pathways for dGpABZ formation in intact cells. 3. Analyze urine benzidine metabolites. Urine from workers exposed to high and low levels of benzidine, as well as from non-exposed workers, will be analyzed using capillary GC/negative ion chemical ionization mass spectrometry. These studies will establish or refute a role for peroxidation in benzidine carcinogenesis, determine pathways involved in initiation of benzidine-induced bladder cancer, contribute to a better understanding of aromatic amine carcinogenesis, and have practical benefits for bladder cancer prevention, biomarkers, and risk assessment.
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