Yamada J, Sakuma M, Ikeda T, Fukuda K, Suga T
Department of Clinical Biochemistry, Tokyo College of Pharmacy, Japan.
Biochim Biophys Acta. 1991 Apr 17;1092(2):233-43. doi: 10.1016/0167-4889(91)90162-q.
Treatment of rats with dehydroepiandrosterone (300 mg/kg body weight, per os, 14 days) caused a remarkable increase in the number of peroxisomes and peroxisomal beta-oxidation activity in the liver. The activities of carnitine acetyltransferase, microsomal laurate 12-hydroxylation, cytosolic palmitoyl-CoA hydrolase, malic enzyme and some other enzymes were also increased. The increases in these enzyme activities were all greater in male rats than in female rats. Immunoblot analysis revealed remarkable induction of acyl-CoA oxidase and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase bifunctional enzyme in the liver and to a smaller extent in the kidney, whereas no significant induction of these enzymes was found in the heart. The increase in the hepatic peroxisomal beta-oxidation activity reached a maximal level at day 5 of the treatment of dehydroepiandrosterone and the increased activity rapidly returned to the normal level on discontinuation of the treatment. The increase in the activity was also dose-dependent, which was saturable at a dose of more than 200 mg/kg body weight. All these features in enzyme induction caused by dehydroepiandrosterone correlate well with those observed in the treatment of clofibric acid, a peroxisome proliferator. Co-treatment of dehydroepiandrosterone and clofibric acid showed no synergism in the enhancement of peroxisomal beta-oxidation activity, suggesting the involvement of a common process in the mechanism by which these compounds induce the enzymes. These results indicate that dehydroepiandrosterone is a typical peroxisome proliferator. Since dehydroepiandrosterone is a naturally occurring C19 steroid in mammals, the structure of which is novel compared with those of peroxisome proliferators known so far, this compound could provide particular information in the understanding of the mechanisms underlying the induction of peroxisome proliferation.
用脱氢表雄酮（300毫克/千克体重，经口给药，共14天）处理大鼠，可使肝脏中过氧化物酶体的数量及过氧化物酶体β-氧化活性显著增加。肉碱乙酰转移酶、微粒体月桂酸12-羟化酶、胞质棕榈酰辅酶A水解酶、苹果酸酶及其他一些酶的活性也有所增加。这些酶活性的增加在雄性大鼠中比在雌性大鼠中更为显著。免疫印迹分析显示，肝脏中酰基辅酶A氧化酶和烯酰辅酶A水合酶/3-羟酰基辅酶A脱氢酶双功能酶有显著诱导，在肾脏中的诱导程度较小，而在心脏中未发现这些酶的显著诱导。在脱氢表雄酮处理的第5天，肝脏过氧化物酶体β-氧化活性增加达到最高水平，停止处理后，增加的活性迅速恢复到正常水平。活性增加也是剂量依赖性的，在剂量超过200毫克/千克体重时达到饱和。脱氢表雄酮引起的酶诱导的所有这些特征与在过氧化物酶体增殖剂氯贝酸处理中观察到的特征密切相关。脱氢表雄酮与氯贝酸共同处理在增强过氧化物酶体β-氧化活性方面未显示协同作用，表明这些化合物诱导酶的机制涉及共同过程。这些结果表明脱氢表雄酮是一种典型的过氧化物酶体增殖剂。由于脱氢表雄酮是哺乳动物中天然存在的C19类固醇，其结构与迄今已知的过氧化物酶体增殖剂相比是新颖的，该化合物可为理解过氧化物酶体增殖诱导的潜在机制提供特殊信息。
