文章基本信息

标题：Substrate Specificity of Human 3(20)α-Hydroxysteroid Dehydrogenase for Neurosteroids and Its Inhibition by Benzodiazepines
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作者：Noriyuki Usami ; Tomohiro Yamamoto ; Syunichi 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：2002
卷号：25
期号：4
页码：441-445
DOI：10.1248/bpb.25.441
出版社：The Pharmaceutical Society of Japan
摘要：In this report, we compared kinetic constants and products in the reduction of the neurosteroids, 3α, 5α-tetrahydroprogesterone (3α,5α-THP) and 3α,5α-tetrahydrodeoxycorticosterone (3α,5α-THDOC), and their precursors, 5α-dihydroprogesterone (5α-DHP), 5α-dihydrodeoxycorticosterone (5α-DHDOC) and progesterone, by three isoenzymes (AKR1C1, AKR1C2 and AKR1C3) of human 3α-hydroxysteroid dehydrogenase. AKR1C1 efficiently reduced 3α,5α-THP, 5α-DHP and progesterone to their 20α-hydroxy metabolites, and slowly converted 5α-DHDOC to 3α,5α-THDOC. AKR1C2 exhibited low 20-ketoreductase activity for 3α,5α-THP and moderate 3-ketoreductase activity for 5α-DHP and 5α-DHDOC. 3α,5α-THDOC was not reduced by the two isoenzymes. No significant activity for the steroids was detected with AKR1C3. The results suggest that AKR1C2 is involved in the neurosteroid synthesis, but AKR1C1 decreases the neurosteroid concentrations in human brain by inactivating 3α,5α-THP and eliminating the precursors from the synthetic pathways. In addition, we found that the several benzodiazepines inhibited the three isoenzymes noncompetitively with respect to the substrate. Although cloxazolam was a potent and specific inhibitor of AKR1C3, diazepam, estazolam, flunitrazepam, medazepam and nitrazepam, that inhibited AKR1C1 and AKR1C2, may influence the neurosteroid metabolism.
关键词：neurosteroid;3α-hydroxysteroid dehydrogenase;20α-hydroxysteroid dehydrogenase;benzodiazepine