Dehydroepiandrosterone supplement increases malate dehydrogenase activity and decreases NADPH-dependent antioxidant enzyme activity in rat hepatocellular carcinogenesis

Abstract

Beneficial effects of dehydroepiandrosterone (DHEA) supplement on age-associated chronic diseases such as cancer, cardiovascular disease, insulin resistance and diabetes, have been reported. However, its mechanism of action in hepatocellular carcinoma in vivo has not been investigated in detail. We have previously shown that during hepatocellular carcinogenesis, DHEA treatment decreases formation of preneoplastic glutathione S-transferase placental form-positive foci in the liver and has antioxidant effects. Here we aimed to determine the mechanism of actions of DHEA, in comparison to vitamin E, in a chemically-induced hepatocellular carcinoma model in rats. Sprague-Dawley rats were administered with control diet without a carcinogen, diets with 1.5% vitamin E, 0.5% DHEA and both of the compounds with a carcinogen for 6 weeks. The doses were previously reported to have anti-cancer effects in animals without known toxicities. With DHEA treatment, cytosolic malate dehydrogenase activities were significantly increased by ~5 fold and glucose 6-phosphate dehydrogenase activities were decreased by ~25% compared to carcinogen treated group. Activities of Se-glutathione peroxidase in the cytotol was decreased significantly with DHEA treatment, confirming its antioxidative effect. However, liver microsomal cytochrome P-450 content and NADPH-dependent cytochrome P-450 reductase activities were not altered with DHEA treatment. Vitamin E treatment decreased cytosolic Se-glutathione peroxidase activities in accordance with our previous reports. However, vitamin E did not alter glucose 6-phosphate dehydrogenase or malate dehydrogenase activities. Our results suggest that DHEA may have decreased tumor nodule formation and reduced lipid peroxidation as previously reported, possibly by increasing the production of NADPH, a reducing equivalent for NADPH-dependent antioxidant enzymes. DHEA treatment tended to reduce glucose 6-phosphate dehydrogenase activities, which may have resulted in limited supply for de novo synthesis of DNA via inhibiting the hexose monophophaste pathway. Although both DHEA and vitamin E effectively reduced preneoplastic foci in this model, they seemed to function in different mechanisms. In conclusion, DHEA may be used to reduce hepatocellular carcinoma growth by targeting NADPH synthesis, cell proliferation and anti-oxidant enzyme activities during tumor growth.

The Anti-Cancer Property of Proteins Extracted from Gynura procumbens (Lour.) Merr

“…Kim et. al (2008) [45] revealed that the activity of malate dehydrogenase is antagonized by the activity of glucose 6-phosphate dehydrogenase in the dehydroepiandrosterone (DHEA) treated hepatocellular carcinoma rats. Glucose 6-phosphate dehydrogenase is the key enzyme regulating the first and irreversible step of pentose phosphate pathway which provides ribose-5-phosphate, a precursor for DNA synthesis in cell proliferation.…”

“…Glucose 6-phosphate dehydrogenase is the key enzyme regulating the first and irreversible step of pentose phosphate pathway which provides ribose-5-phosphate, a precursor for DNA synthesis in cell proliferation. The demand for ribose-5-phosphates for de novo synthesis of DNA has been shown to increase during the promotion phase of carcinogenesis [45]. Therefore the high abundance of malate dehydrogenase may cause a suppressive effect on the generation of ribose-5-phasphates in MDA-MB-231 cells which in turn leads to suppression of cell proliferation.…”