Hepatic gene mutations induced in Big Blue rats by both the potent rat liver azo-carcinogen 6BT and its reported noncarcinogenic analogue 5BT.
The potent rat liver carcinogen 6-p-dimethylaminophenylazobenzthiazole (6BT) and its reported noncarcinogenic analogue 5-p-dimethylaminophenylazobenzthiazole (5BT; evaluated for carcinogenicity under the similar limited bioassay conditions used for 6BT) have been studied in order to seek an explanation for their different carcinogenic activities. Both compounds act as DNA-damaging agents to the rat liver, and both have now been shown to induce lacI (-) gene mutations in the liver of Big Blue(trade mark) transgenic rats. Both compounds were mutagenic following ten daily gavage doses or following administration 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 noncarcinogen 5BT, caused proliferation of oval stem cells in the livers by both routes of administration. It is possible that mutations induced in oval cells by 6BT are responsible for its potent carcinogenicity, and that the comparative absence of these cells in 5BT-treated livers may account for the carcinogenic inactivity of 5BT. Equally, the proliferation of the oval cells may reflect changes in liver homeostasis associated with the liver toxicity observed at the dose level of 6BT used (which was, nonetheless, the dose level used in the positive 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 assessed for this activity.
Fletcher
K
K
Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ United Kingdom.
Soames
A R
AR
Tinwell
H
H
Lefevre
P A
PA
Ashby
J
J
D000818:Animals; D052160:Benzothiazoles; D002273:Carcinogens / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008297:Male; D009154:Mutation; D051381:Rats; D013844:Thiazoles / Q000494:pharmacology*; D004124:p-Dimethylaminoazobenzene / Q000031:analogs & derivatives* / Q000494:pharmacology
C400102:5-p-dimethyl-aminophenylazobenzthiazole; D052160:Benzothiazoles; D002273:Carcinogens; D013844:Thiazoles; C012103:N,N-dimethyl-4-(6-benzothiazolylazo)aniline; D004124:p-Dimethylaminoazobenzene