Induction of microsomal NADPH-cytochrome P-450 reductase and cytochrome P-450IVA1 (P-450LA omega) by dehydroepiandrosterone in rats: a possible peroxisomal proliferator.
Induction of microsomal NADPH-cytochrome P-450 reductase and cytochrome P-450IVA1 (P-450LA omega) by dehydroepiandrosterone in rats: a possible peroxisomal proliferator.
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发表时间：
1989-05
期刊：
影响因子：
11.2
通讯作者：
H. Q. Wu;J. Masset-Brown;D. Tweedie;L. Milewich;R. Frenkel;C. Martin-Wixtrom;R. Estabrook;R. Prough
中科院分区：
文献类型：
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作者：
H. Q. Wu;J. Masset-Brown;D. Tweedie;L. Milewich;R. Frenkel;C. Martin-Wixtrom;R. Estabrook;R. Prough
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已被证明可以抑制结肠、肝脏和肺部的化学致癌作用。因此，我们评估了DHEA对与致癌物代谢相关的肝酶活性的影响。用含0.45%DHEA(w/w)的合成饲料喂养雄性SD大鼠，可使微粒体NADPH-细胞色素P-450还原酶活性和细胞色素b5含量分别增加1.8倍和1.4倍。在饲养第7天，微粒体细胞色素P-450的总含量、微粒体NADH-细胞色素b5还原酶和细胞质或微粒体NAD(P)H-苯二酚氧化还原酶的活性均未见明显变化。胞内谷胱甘肽S转移酶活性降至对照的68%。DHEA PO的管理或通过IP。注射5d可诱导相同程度的NADPH-细胞色素P-450还原酶活性。这种黄素蛋白还原酶的最大诱导量出现在饲喂后的第3至4天或80-120 mg/kg的剂量下。腹腔注射脱氢表雄酮后，微粒体细胞色素P-450的含量略有增加，但有统计学意义。与对照组相比，饲喂DHEA的大鼠生长速度较慢，而注射DHEA的大鼠的生长速度较慢。与对照组的增长率相同。口服脱氢表雄酮对大鼠肝脏重量的影响或者IP。与对照组大鼠相比，路径数显著增加。用含DHA或对照的饲料配对喂养大鼠，结果表明，肝微粒体NADPH-细胞色素P-450还原酶和至少一种形式的细胞色素P450(P-450IVA1)的诱导水平与饲喂DHEA的大鼠肝脏中的水平相同。这一发现表明，黄素蛋白和至少一种形式的细胞色素的诱导不是由于热量限制。给药前后大鼠肝微粒体NADPH-细胞色素P-450还原酶含量均有不同程度的升高。用Western blotting技术观察DHEA的表达。脱氢表雄酮似乎不能诱导大鼠肝微粒体细胞色素P-450的任何主要形式，而这些主要形式通常是由苯巴比妥、β-萘黄酮或地塞米松在体内预处理所增加的。然而，对雄烯二酮和睾酮代谢的体外测定显示，喂食DHEA后，肝微粒体的16α-羟基酶活性显著降低。
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)