Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul 151-742, Korea.
Nutr Res Pract. 2008 Summer;2(2):80-4. doi: 10.4162/nrp.2008.2.2.80. Epub 2008 Jun 30.
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.
已有报道称，脱氢表雄酮（DHEA）补充剂对癌症、心血管疾病、胰岛素抵抗和糖尿病等与年龄相关的慢性疾病有有益影响。然而，其在体内肝细胞癌中的作用机制尚未得到详细研究。我们之前的研究表明，在肝细胞癌发生过程中，DHEA 处理可减少肝脏中前致癌性谷胱甘肽 S-转移酶胎盘形式阳性灶的形成，并具有抗氧化作用。在这里，我们旨在确定 DHEA 与维生素 E 在大鼠化学诱导的肝细胞癌模型中的作用机制。Sprague-Dawley 大鼠给予不含致癌物的对照饮食、含 1.5%维生素 E 的饮食、含 0.5%DHEA 的饮食和含致癌物及上述两种化合物的饮食，共 6 周。这些剂量先前在动物中报道具有抗癌作用，且无已知毒性。与致癌物处理组相比，DHEA 处理组的胞质苹果酸脱氢酶活性显著增加了约 5 倍，葡萄糖 6-磷酸脱氢酶活性降低了约 25%。DHEA 处理可显著降低细胞溶质中 Se-谷胱甘肽过氧化物酶的活性，证实了其抗氧化作用。然而，DHEA 处理并未改变肝微粒体细胞色素 P-450 含量和 NADPH 依赖性细胞色素 P-450 还原酶的活性。维生素 E 处理降低了与我们之前的报告一致的胞质 Se-谷胱甘肽过氧化物酶活性。然而，维生素 E 并未改变葡萄糖 6-磷酸脱氢酶或苹果酸脱氢酶的活性。我们的结果表明，DHEA 可能通过增加 NADPH 的产生，一种 NADPH 依赖性抗氧化酶的还原当量，从而减少肿瘤结节的形成和脂质过氧化，正如之前报道的那样。DHEA 处理有降低葡萄糖 6-磷酸脱氢酶活性的趋势，这可能通过抑制己糖单磷酸途径导致用于 DNA 从头合成的供应有限。尽管 DHEA 和维生素 E 都能有效地减少该模型中的前致癌灶，但它们似乎作用于不同的机制。总之，DHEA 可通过在肿瘤生长过程中靶向 NADPH 合成、细胞增殖和抗氧化酶活性来减少肝细胞癌的生长。
