N GLUCURONIDATION OF BENZIDINE & ITS METABOLITES ROLE IN BLADDER CANCER

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Workers exposed to a high levels of benzidine have a 100-fold increased incidence of bladder cancer. This review evaluates the overall metabolism of benzidine to determine pathways important to initiation of bladder cancer. Upon incubation of benzidine with liver slices from rat, dog, and human, different proportions of this diamine were N-acetylated and N-glucuronidated. With dog, a non-acetylator, N-glucuronidation was the major pathway. In contrast, little glucuronidation was observed in rat with N,N/-diacetylbenzidine the major metabolite. Human liver slices demonstrated both extensive N-acetylation and N-glucuronidation. Differences between rat and human were attributed to rapid deacetylation by human liver with N-acetylbenzidine rather than N,N/-diacetylbenzidine accumulating. N-Acetylbenzidine oxidative metabolism was also observed. The acid lability of glucuronide products of benzidine, N-acetylbenzidine, and oxidation products of N-acetylbenzidine m etabolism was assessed. N-Glucuronides of benzidine, N-acetylbenzidine, and N'-hydroxy-N-acetylbenzidine were acid labile with the latter having a much longer t1/2 than the former two glucuronides. Because bladder epithelium contains relatively high levels of prostaglandin H synthase and not cytochrome P-450, peroxidative metabolism of N-acetylbenzidine was assessed. N'-(3'-Monophospho-deoxyguanosin-8-yl)-N-acetylbenzidine was the only DNA adduct detected. This adduct is also the major adduct detected in bladder cells from workers exposed to benzidine. In urine from these workers, an inverse relationship between urine pH and levels of free (unconjugated) benzidine and N-acetylbenzidine was observed. A similar inverse relationship was observed for urine pH and levels of bladder cell N'-(3'-monophospho-deoxyguanosin-8-yl)-N-acetylbenzidine. These results suggest multiple pathways (acetylation, glucuronidation, peroxidation) in multiple organs (liver, blood, kidney, bladder) are important in benzidine-induced bladder cancer.