Promotive effects of steroids and bile acids on hepatocarcinogenesis initiated by diethylnitrosamine.

The ability of four steroids and three bile acids to promote the appearance of hyperplastic foci and hyperplastic nodules initiated by diethylnitrosamine (DEN) in the liver of male Fischer rats was tested and compared with that of the known promoter phenobarbital (PB, 0.05%) as a standard value. Two weeks after a single dose of 200 mg of DEN per kg, the animals were exposed to test chemicals for 10 weeks. At 4 weeks following DEN, all treatment groups were subjected to partial hepatectomy. Of the steroids tested at the maximum tolerable doses, as determined in preliminary experiments, ethinyl estradiol was the most potent promoter, inducing more hyperplastic nodules than did PB and almost 50% less gamma-glutamyl transpeptidase-positive foci. However, gamma-glutamyl transpeptidase-positive foci induced by ethinyl estradiol were twice the average size as those induced by PB. The steroids testosterone, cortisone, and dexamethasone induced more foci than did DEN alone, but few if any hyperplastic nodules. Deoxycholic acid was the most potent promoter of the bile acids tested, including 3 to 4 times more hyperplastic nodules than did PB and more gamma-glutamyl transpeptidase-positive foci, which were 5 times larger on the average than those induced by PB. The other bile acids tested, lithocholic acid and taurine, induced slightly more foci than did DEN alone but no hyperplastic nodules. These findings suggest that ethinyl estradiol and deoxycholic acid are relatively strong promoters of the appearance of preneoplastic lesions in hepatocarcinogenesis.