文章基本信息

标题：Dual Effects of Anti-inflammatory 2-Arylpropionic Acid Derivatives on a Major Isoform of Human Liver 3α-Hydroxysteroid Dehydrogenase
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作者：Tomohiro YAMAMOTO ; Kazuya MATSUURA ; Shunichi SHINTANI 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：1998
卷号：21
期号：11
页码：1148-1153
DOI：10.1248/bpb.21.1148
出版社：The Pharmaceutical Society of Japan
摘要：Nonsteroidal anti-inflammatory drugs have been shown to be potent inhibitors of mammalian 3α-hydroxy-steroid dehydrogenase. Here, we report that the drugs of the 2-arylpropionic acid class act as both activators and inhibitors for a predominant isoform of the human liver enzyme which is involved in the metabolism of steroid hormones, bile acids, drug ketones and xenobiotic aromatic hydrocarbons. Flurbiprofen, fenoprofen, ibuprofen, naproxen, ketoprofen and suprofen stimulated the activity of the human enzyme (1.5-2.4-fold) at low concentrations of less than 20-100 μM, whereas at higher concentrations they inhibited the acitivity. Comparison of the effects of the structurally related compounds with the drugs revealed that the essential structure required as the activator molecule is 2-phenylpropionic acid with a hydrophobic substituent on the aromatic ring. In addition, an R-enantiomer of ibuprofen showed higher activation (3-fold) than its S-enantiomer. Kinetic analysis with respect to NADP⁺ concentration indicated that R- and S-ibuprofens are nonessential activators showing binding constants of 23 and 34 μM, respectively. Neither enantiomers activated, but rather inhibited the enzyme, with Met replacing Arg-276 which has been shown to interact with the 2'-phophate of NADP⁺. The inhibitions of the mutant enzyme by R- and S-ibuprofens were competitive with respect to the substrate, giving K_i values of 95 and 18 μM, respectively. The results suggest that the human liver 3α-hydroxysteroid dehydrogenase isoform possesses the two distinct sites, activator and inhibitor sites, to which anti-inflammatory 2-arylpropionates stereoselectively bind.
关键词：3α-hydroxysteroid dehydrogenase;anti-inflammatory drug;activation;stereoselectivity;aldo-keto reductase family