非那雄胺
二氢睾酮
类固醇
还原酶
生物
酶
生物化学
雄激素受体
突变体
错义突变
前列腺癌
雄激素
化学
突变
基因
前列腺
遗传学
癌症
激素
作者
Nick Makridakis,E. Di Salle,Juergen K.V. Reichardt
出处
期刊:Pharmacogenetics
[Ovid Technologies (Wolters Kluwer)]
日期:2000-07-01
卷期号:10 (5): 407-413
被引量:196
标识
DOI:10.1097/00008571-200007000-00004
摘要
Human prostatic steroid 5α-reductase, encoded by the SRD5A2 gene on chromosome band 2p23, catalyses the irreversible conversion of testosterone to dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH as its cofactor. This enzyme has never been purified but a number of competitive inhibitors have been developed for this enzyme since increased steroid 5α-reductase activity may cause benign prostatic hypertrophy and prostate cancer. We report here the detailed biochemical and pharmacogenetic dissection of the human enzyme by analysing 10 missense substitutions and three double mutants which are all naturally found in humans. Nine of these 13 mutants reduce activity (measured as Vmax) by 20% or more, three increase steroid 5α-reductase by more than 15% and one results in essentially unaltered kinetic properties suggesting that it is a truly neutral (`polymorphic') amino acid substitution. Substantial pharmacogenetic variation among the mutants was also observed when three competitive inhibitors, finasteride, GG745 (dutasteride) and PNU157706, were investigated. Our studies not only define the substrate and cofactor binding sites of human steroid 5α-reductase, but also have significant consequences for the pharmacological usage of steroid 5α-reductase inhibitors in human patients treated for prostatic conditions.
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