Hepatic gene mutations induced in Big Blue (TM) rats by both the potent rat liver azo-carcinogen 6BT and its reported noncarcinogenic analogue 5BT

The potent rat liver carcinogen 6-p-dimethyl-aminophenylazobenzthiazole (6B T) and its reported noncarcinogenic analogue 5-p-dimethyl-aminophenylazoben zthiazole (5BT; evaluated for carcinogenicity under the similar limited bio assay conditions used for 6BT) have been studied in order to seek an explan ation for their different carcinogenic activities. Both compounds act as DN A-damaging agents to the rot liver, and both have now been shown to induce lacl(-) gene mutations in the liver of Big Blue(TM) transgenic rots. Both c ompounds were mutagenic following ten daily gavage doses or following admin istration in diet for 10 days. Neither chemical induced cell proliferation in the liver following repeat gavage administrations. In contrast, dietary administration of 6BT, and to a lesser extent of 5BT, induced hepatic cell proliferation. The carcinogen 6BT, but not the non-carcinogen 5BT, caused p roliferation of oval stem cells in the livers by both routes of administrat ion. it is possible that mutations induced in oval cells by 6BT are respons ible For its potent carcinogenicity, and that the comparative absence of th ese cells in 5BT-treated livers may account for the carcinogenic inactivity of 5BT. Equally, the proliferation of the oval cells may reflect changes i n liver homeostasis associated with the liver toxicity observed at the dose level of 6BT used (which was, nonetheless, the dose level used in the posi tive cancer bioassays), it is concluded that the new data presented cannot explain the differing carcinogenic activities of 5BT and 6BT, and that the reported noncarcinogen 5BT may also be carcinogenic when adequately assesse d for this activity. (C) 1999 Wiley-Liss, Inc.