Arlotto M P, Sonderfan A J, Klaassen C D, Parkinson A
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66103.
Biochem Pharmacol. 1987 Nov 15;36(22):3859-66. doi: 10.1016/0006-2952(87)90450-3.
Treatment of rats with pregnenolone-16 alpha-carbonitrile (PCN) markedly induces rat liver microsomal cytochrome P-450p and UDP-GT-dt1, a glucuronosyltransferase active towards the digitoxin metabolite, digitoxigenin monodigitoxoside. The present study characterizes the regulation of these two enzymes in rats treated with different xenobiotics. Like PCN, treatment of rats with dexamethasone, spironolactone, troleandomycin or erythromycin estolate markedly induced both UDP-GT-dt1 and cytochrome P-450p (measured as erythromycin demethylase and testosterone 2 beta-, 6 beta-, 15 beta-, and 18-hydroxylase activities). However, compared to PCN and dexamethasone, both troleandomycin and erythromycin estolate preferentially induced cytochrome P-450p, whereas spironolactone preferentially induced UDP-GT-dt1. Treatment of rats with the polychlorinated biphenyl mixture, Aroclor 1254, increased both cytochrome P-450p and UDP-GT-dt1 activity to about 40% of that in liver microsomes from rats induced with PCN or dexamethasone. Treatment of rats with phenobarbital or chlordane caused a relatively small increase in cytochrome P-450p and UDP-GT-dt1 activity. Neither enzyme was induced by treatment of rats with 3-methylcholanthrene, rifampin or digitoxin. The induction of cytochrome P-450p and UDP-GT-dt1 by PCN followed similar dose-response curves. Although cytochrome P-450p and UDP-GT-dt1 are differentially affected by the age and the sex of rats, the enzymes responded similarly, but not identically, to xenobiotic treatment. This suggests that cytochrome P-450p and UDP-GT-dt1 are co-inducible but not coordinately regulated.
用孕烯醇酮 -16α - 腈（PCN）处理大鼠可显著诱导大鼠肝脏微粒体细胞色素P - 450p和UDP - GT - dt1，UDP - GT - dt1是一种对洋地黄毒苷代谢物洋地黄毒苷元单洋地黄毒糖苷具有活性的葡糖醛酸基转移酶。本研究对用不同外源化学物处理的大鼠中这两种酶的调节特性进行了表征。与PCN一样，用地塞米松、螺内酯、三乙酰竹桃霉素或无味红霉素处理大鼠可显著诱导UDP - GT - dt1和细胞色素P - 450p（以红霉素脱甲基酶和睾酮2β -、6β -、15β - 和18 - 羟化酶活性来衡量）。然而，与PCN和地塞米松相比，三乙酰竹桃霉素和无味红霉素都优先诱导细胞色素P - 450p，而螺内酯优先诱导UDP - GT - dt1。用多氯联苯混合物Aroclor 1254处理大鼠，可使细胞色素P - 450p和UDP - GT - dt1活性增加至用PCN或地塞米松诱导的大鼠肝脏微粒体中相应活性的约40%。用苯巴比妥或氯丹处理大鼠会使细胞色素P - 450p和UDP - GT - dt1活性有相对较小的增加。用3 - 甲基胆蒽、利福平或洋地黄毒苷处理大鼠均未诱导这两种酶。PCN对细胞色素P - 450p和UDP - GT - dt1的诱导遵循相似的剂量反应曲线。尽管细胞色素P - 450p和UDP - GT - dt1受大鼠年龄和性别的影响不同，但这两种酶对外源化学物处理的反应相似但不完全相同。这表明细胞色素P - 450p和UDP - GT - dt1是共同可诱导的，但不是协同调节的。
