DEHYDROEPIANDROSTERONE IS A COMPLETE HEPATOCARCINOGEN AND POTENT TUMOR PROMOTER IN THE ABSENCE OF PEROXISOME PROLIFERATION IN RAINBOW-TROUT

Dehydroepiandrosterone (DHEA), fed for 30 weeks to rainbow trout after initiation with the hepatocarcinogen aflatoxin B-1 (AFB(1)), produced a dose-dependent enhancement of carcinogenesis as measured by increas ed tumor incidence, multiplicity and size, Significant enhancement was observed at 222 p,p,m,, which corresponds to a daily dosage one-half that previously administered to humans in clinical trials, DHEA was al so capable of acting as a complete carcinogen in this model, producing liver tumors at doses as low as 222-444 p,p,m, Tumors isolated from t rout treated with DHEA alone contained mutations in Ki-ras, primarily codon 12[1] G-->A transitions, providing the first suggestive evidence that DHEA could be a genotoxic carcinogen, The carcinogenicity of DHE A in trout is independent of peroxisome proliferation, as measurements of peroxisomal beta-oxidation and catalase activity support previous observations that trout, like humans, are weak responders to peroxisom e proliferators.