Hepatocarcinogenicity of Dehydroepiandrosterone in the Rat1

Dehydroepiandrosterone, a major secretory steroid hormone of the human adrenal gland, possesses mitoinhibitory and anticarcinogenic properties. It also induces peroxisome proliferation in the livers of rats and mice. Because peroxisome proliferators exhibit hepatocarcinogenic potential, it is necessary to examine the long term hepatic effects of dehydroepiandrosterone since this hormone is contemplated for use as a potential cancer chemopreventive agent in humans. Dehydroepiandros terone was administered in the diet at a concentration of 0.45% to F-344 rats for up to 84 weeks. At the termination of the experiment, 14 of 16 rats developed hepatocellular carcinomas. Liver tumors induced by de hydroepiandrosterone lacked •¿ v-glutamyl transpeptidase and glutathione S-transferase (placenta! form); these phenotypic properties are identical to the features exhibited by liver tumors induced by other peroxisome proliferators. Dehydroepiandrosterone was also shown to markedly in hibit liver cell |3H]thymidine labeling indices, suggesting that cell prolif eration is not a critical feature in liver tumor development with this agent. These results show that although dehydroepiandrosterone exerts anticar cinogenic effects in a variety of tissues, the peroxisome-proliferative property makes it a hepatocarcinogen.