4-羟基雄甾-4-烯-3,17-二酮及其代谢产物对5α-还原酶活性和雄激素受体的影响。

Effects of 4-hydroxyandrost-4-ene-3,17-dione and its metabolites on 5 alpha-reductase activity and the androgen receptor.

作者信息

Davies J H, Shearer R J, Rowlands M G, Poon G K, Houghton J, Jarman M, Dowsett M

机构信息

Department of Urology, St. Georges Hospital, London, England, UK.

出版信息

J Enzyme Inhib. 1992;6(2):141-7. doi: 10.3109/14756369209040745.

DOI:10.3109/14756369209040745

PMID:1284430

Abstract

The steroidal aromatase inhibitor, 4-hydroxyandrost-4-ene-3,17-dione (4OHA) and its metabolites, 4-hydroxytestosterone (4OHT), 3 beta,17-dihydroxy-5 alpha-androstan-4-one (metabolite A) and 3 alpha, 17-dihydroxy-5 beta-androstan-4-one (metabolite B) were evaluated as inhibitors of the human prostatic 5 alpha-reductase enzyme and for binding to the rat prostatic androgen receptor. 4OHA and 4OHT were weak inhibitors of 5 alpha-reductase with IC50 values of 15-29 microM. Metabolites A and B had no significant inhibitory activity. 4OHA and metabolites A and B bound weakly to the androgen receptor. The binding affinities (RBA) relative to mibolerone (RBA = 100) were 0.085, 0.485 and 0.016, respectively. However, 4OHT (RBA = 75) was a more potent binder than the endogenous androgen 5 alpha-dihydrotestosterone (RBA = 66). The ability of these metabolites, in particular 4OHT, to bind to the androgen receptor may explain the in vivo androgenic activity of 4OHA.

摘要

甾体芳香化酶抑制剂4-羟基雄甾-4-烯-3,17-二酮（4OHA）及其代谢产物4-羟基睾酮（4OHT）、3β,17-二羟基-5α-雄甾烷-4-酮（代谢产物A）和3α,17-二羟基-5β-雄甾烷-4-酮（代谢产物B）被评估作为人前列腺5α-还原酶的抑制剂以及与大鼠前列腺雄激素受体的结合能力。4OHA和4OHT是5α-还原酶的弱抑制剂，IC50值为15 - 29微摩尔。代谢产物A和B没有显著的抑制活性。4OHA以及代谢产物A和B与雄激素受体的结合较弱。相对于米勃酮（RBA = 100）的结合亲和力（RBA）分别为0.085、0.485和0.016。然而，4OHT（RBA = 75）比内源性雄激素5α-双氢睾酮（RBA = 66）具有更强的结合能力。这些代谢产物，特别是4OHT，与雄激素受体结合的能力可能解释了4OHA的体内雄激素活性。