Wu H Q, Masset-Brown J, Tweedie D J, Milewich L, Frenkel R A, Martin-Wixtrom C, Estabrook R W, Prough R A
Department of Biochemistry, School of Medicine, University of Louisville, Kentucky 40292.
Cancer Res. 1989 May 1;49(9):2337-43.
Dehydroepiandrosterone (DHEA) is a naturally occurring C19-steroid that is found in the peripheral circulation of mammals, including humans. The feeding of DHEA to rodents has been shown to inhibit chemical carcinogenesis in colon, liver, and lung. Therefore, the effect of DHEA on hepatic enzyme activities that are associated with carcinogen metabolism was assessed. Microsomal NADPH-cytochrome P-450 reductase activity and the content of cytochrome b5 were induced 1.8- and 1.4-fold, respectively, upon feeding male Sprague-Dawley rats a synthetic diet containing 0.45% DHEA (w/w). No significant changes in total content of microsomal cytochrome P-450 or the activities of microsomal NADH-cytochrome b5 reductase and cytosolic or microsomal NAD(P)H-quinone oxidoreductase were noted at day 7 of feeding. Cytosolic glutathione S-transferase activity was decreased to 68% of control activity. Administration of DHEA p.o. or by i.p. injection for 5 days led to the same extent of induction of NADPH-cytochrome P-450 reductase activity. Maximal induction of this flavoprotein reductase was noted between days 3 and 4 of feeding or at a dose of 80-120 mg/kg i.p. A small but statistically significant increase in total microsomal cytochrome P-450 was observed after DHEA administration i.p. Rats fed DHEA had a slower growth rate compared with rats fed control diet, whereas rats treated with DHEA i.p. had growth rates identical to those of controls. The liver weights of rats given DHEA by p.o. or i.p. routes were increased significantly compared to those of control rats. Pair feeding of rats with DHA-containing or control diets served to demonstrate that the levels of induction of hepatic microsomal NADPH-cytochrome P-450 reductase and at least one form of cytochrome P450 (P-450IVA1) were the same as those seen in livers of rats fed DHEA ad libitum. This finding suggested that the induction of the flavoprotein and at least one form of the cytochrome was not due to caloric restriction. The increase in NADPH-cytochrome P-450 reductase content of liver microsomes prepared from rats either fed or treated i.p. with DHEA was also observed by Western blotting techniques. DHEA did not appear to induce any of the major forms of rat liver microsomal cytochrome P-450 that are normally increased by either phenobarbital, beta-naphthoflavone, or dexamethasone pretreatment of rats in vivo. However, the measurement of androstenedione and testosterone metabolism in vitro showed pronounced decreases in the 16 alpha-hydroxylase activities of liver microsomes following DHEA feeding.(ABSTRACT TRUNCATED AT 400 WORDS)
脱氢表雄酮（DHEA）是一种天然存在的C19类固醇，存在于包括人类在内的哺乳动物的外周循环中。给啮齿动物喂食DHEA已被证明可抑制结肠、肝脏和肺部的化学致癌作用。因此，评估了DHEA对与致癌物代谢相关的肝酶活性的影响。给雄性Sprague-Dawley大鼠喂食含0.45%（w/w）DHEA的合成饮食后，微粒体NADPH-细胞色素P-450还原酶活性和细胞色素b5含量分别诱导了1.8倍和1.4倍。喂食第7天时，微粒体细胞色素P-450的总含量、微粒体NADH-细胞色素b5还原酶以及胞质或微粒体NAD(P)H-醌氧化还原酶的活性均未发现显著变化。胞质谷胱甘肽S-转移酶活性降至对照活性的68%。口服或腹腔注射DHEA 5天导致NADPH-细胞色素P-450还原酶活性的诱导程度相同。这种黄素蛋白还原酶的最大诱导在喂食第3至4天或腹腔注射剂量为80 - 120 mg/kg时出现。腹腔注射DHEA后，观察到微粒体细胞色素P-450总量有小幅但具有统计学意义的增加。与喂食对照饮食的大鼠相比，喂食DHEA的大鼠生长速度较慢，而腹腔注射DHEA处理的大鼠生长速度与对照组相同。经口服或腹腔注射给予DHEA的大鼠肝脏重量与对照大鼠相比显著增加。将喂食含DHA或对照饮食的大鼠配对饲养表明，肝脏微粒体NADPH-细胞色素P-450还原酶和至少一种细胞色素P450（P-450IVA1）的诱导水平与自由采食DHEA的大鼠肝脏中所见水平相同。这一发现表明黄素蛋白和至少一种细胞色素的诱导并非由于热量限制。通过蛋白质印迹技术也观察到，无论是喂食还是腹腔注射DHEA的大鼠制备的肝脏微粒体中，NADPH-细胞色素P-450还原酶含量均增加。DHEA似乎并未诱导大鼠肝脏微粒体细胞色素P-450的任何主要形式，而这些形式在体内经苯巴比妥、β-萘黄酮或地塞米松预处理的大鼠中通常会增加。然而，体外雄烯二酮和睾酮代谢的测定显示，喂食DHEA后肝脏微粒体的16α-羟化酶活性显著降低。（摘要截短于400字）
