Benzidine N-Glucuronidation by Human, Rat, and Dog Liver

Hepatic N-glucuronidation is proposed to be an important pathway for metabolism of aromatic amine carcinogens and was assessed in human, rat, and dog. Benzidine and its monoacetylated product N-acetylbenzidine were glucuronidated. The latter was identified as an N’-glucuronide. Both glucuronides were acid labile with t1/2s of approximately 5 min at pH 5.3 and 37 °C. In plasma, the stability of both glucuronides increased. Irrespective of the detergent used to increase microsomal activity, the relative amount of glucuronidation was human > dog > rat N-Glucuronidation of N-diacetylbenzidine was not detected. Following incubation with ³H-benzidine, liver slices from all three species produced N-glucuronides. However, only human and rat slices produced N-acetylbenzidine N’-glucuronide. The stability of these N-glucuronides in plasma and their lability in acidic urine provides a mechanism by which these detoxified products are transported to the bladder and then recycled to the arylamine. A model is presented illustrating the effect of N-glucuronidation and the influence of N-acetylation on arylmono- and aryldi- amine-induced bladder carcinogenesis.