Comparison of the promoting effects of various agents in induction of preneoplastic lesions in rat liver.

The promoting activities of 29 compounds on induction of hyperplastic (neoplastic) liver nodules (HN) and the dose-dependent effects of tumor promoting agents were compared by using a short-term test system developed in this laboratory. In tests on promoting activity, F344 rats were given a single dose (200 mg/kg) of N-nitrosodiethylamine (DEN), and from two weeks later, were treated with various test compounds for 6 or 10 weeks. They were subjected to partial hepatectomy 3 or 4 weeks after DEN treatment. The results showed that strong hepatocarcinogens, such as aflatoxin B1, DEN, N-nitrosodimethylamine (DMN), 2-acetylaminofluorene (2-AAF), 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) and ethionine, induced many hyperplastic liver nodules, whereas dieldrin, 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT), polychlorinated biphenyls (PCB) and alpha-hexachlorocyclohexane (alpha-HCH) induced few lesions. Nonhepatocarcinogens, such as N-nitrosoethylurea (ENU) and 3-methylcholanthrene (3-MC), only slightly induced hyperplastic nodules. Of the miscellaneous compounds tested, phenobarbital, deoxycholic acid and ethynyl estradiol also induced gamma-glutamyl transpeptidase (gamma-GT) positive foci. In tests on the dose-dependent effects of promoting agents, DMN was given at different concentrations for 6 weeks from 2 weeks after DEN treatment. Results were quantitated by histochemical measurement of the number or area of gamma-GT positive lesions induced. A long-term experiment on the effect of feeding DMN for 96 weeks was also done. Clear dose-dependent effects of DMN were seen in induction of gamma-GT positive foci in the short-term experiment and neoplastic lesions in the long-term one.