Organ, species, and compound specificity in the metabolic activation of primary aromatic amines

For the evaluation of the role of target tissue activation in the induction of bladder cancer, microsome-mediated N-hydroxylation of the bladder carcinogen 4-biphenylamine (4-BA) was studied in bovine and canine bladder mucosae, relative to the activity in liver. Bovine bladder microsomes mediated the N-hydroxylation of 4-BA at an exceptionally high rate, whereas no detectable activity was found with bovine liver microsomes. Dog bladder microsomes were 40-100 times less active than bovine bladder microsomes and contained approximately one-third the amount of cytochrome P450. Dog liver microsomes were as active as dog bladder microsomes per nanomole P450 and an order of magnitude more active when normalized to microsomal protein. Rat liver microsomes contained the highest level of P450 of all the preparations studied, and N-hydroxylase activity was approximately twice the rate of that of dog liver. The rate of N-hydroxylation of 2-naphthylamine (2-NA) and 1-naphthylamine (1-NA) was compared in bovine bladder mucosa and was found to correlate well with the relative potency of these compounds as bladder carcinogens (4-BA greater than 2-NA greater than 1-NA). Such a comparison could not be made with dog bladder mucosa because of its low N-hydroxylation activity. In addition, bovine bladder mucosa S-9 mutagenic activation of 4-BA, 2-NA, and 1-NA was investigated in Salmonella typhimurium and found to parallel the carcinogenic potency of these compounds. These results demonstrate considerable tissue, species, and compound specificity for the metabolic activation of aromatic amines and provide further evidence in support of bladder activation as a mechanism of aromatic amine-induced bladder cancer.