Carcinogenic and anticarcinogenic effects of dehydroepiandrosterone in the liver of male and female rats

Abstract

Dehydroepiandrosterone (DHEA), an adrenal steroid in humans, shows a certain anticarcinogenic effect in rat liver when it is administered simultaneously with strong carcinogens such as N-nitrosomorpholine (NNM). On the other hand, DHEA is an hepatocarcinogen in the rat when administered at high doses for more than 18 months. The hepatocellular tumors arise from amphophilic cell foci and exhibit a well-differentiated pheno-type. Wlien administered subsequent to NNM, DHEA acts as a tumor promoter in rat liver. Preneoplastic lesions of the glycogenotic/basophilic cell lineage induced by NNM are modulated to amphophilic lesions by DHEA. Female animals are more sensitive than males in respect of the carcinogenic and tumor-enhancing effect of DHEA. The higher sensitivity in females may be due to higher blood levels of DHEA andlor different metabolism and elimination of the drug, as compared to males. DHEA markedly induces cytochrome P450IVA, particularly in the liver of male rats. This effect may explain the rapid metabolism and elimination of the substance and the lower carcinogenicity in males. Both preneoplastic amphophilic foci and neoplasms are characterized by a strong proliferation of mitochondria. DHEA also induces peroxisome proliferation and susceptibility to lipid peroxidation in both genders. Furthermore, DHEA causes a reduction in activity and expression of key enzymes of carbohydrate metabolism and of glycogen content in the liver, which may be related to modulation of hepatocarcinogenesis.