Kojo H, Nakayama O, Hirosumi J, Chida N, Notsu Y, Okuhara M
Exploratory Research Laboratory, Fujisawa Pharmaceutical Co., Ltd, Tsukuba, Japan.
Mol Pharmacol. 1995 Sep;48(3):401-6.
Recent cloning of the cDNAs for the two isozymes of steroid 5 alpha-reductase (EC 1.3.99.5) allowed individual expression of the isozymes and permitted us to investigate the action of steroid 5 alpha-reductase inhibitors against the individual isozymes without any ambiguity that may be caused by coexistence of the isozymes in tissue preparations. We examined the kinetic characteristics of FK143 (4-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]-1H-indol-1- yl]butyric acid), a novel nonsteroidal steroid 5 alpha-reductase inhibitor against cloned human and rat steroid 5 alpha-reductase isozymes. FK143 was shown to inhibit both isozymes equally. The mode of the inhibition of FK143 against both isozymes was noncompetitive. The inhibition constants Kie and Kies of FK143 for human types 1 and 2 were 27.0 and 19.6 nM and 19.9 and 14.5 nM, respectively. Species selectivity between human and rat of the inhibitory activity of FK143 against both isozymes was not found. We also examined the effect of FK143 on the in vivo expression of the genes encoding for the rat steroid 5 alpha-reductase isozymes. FK143 reduced the testosterone-induced increase in the amount of the type 1 mRNA in castrated rat, whereas it did not substantially affect the amount of the type 2 mRNA.
最近，类固醇5α-还原酶（EC 1.3.99.5）的两种同工酶的cDNA被克隆出来，这使得同工酶能够单独表达，并且让我们能够研究类固醇5α-还原酶抑制剂对各个同工酶的作用，而不会因组织制剂中同工酶的共存而产生任何歧义。我们研究了新型非甾体类固醇5α-还原酶抑制剂FK143（4-[3-[3-[双（4-异丁基苯基）甲基氨基]苯甲酰基]-1H-吲哚-1-基]丁酸）对克隆的人及大鼠类固醇5α-还原酶同工酶的动力学特性。结果表明，FK143对两种同工酶的抑制作用相同。FK143对两种同工酶的抑制模式均为非竞争性。FK143对人1型和2型同工酶的抑制常数Kie和Kies分别为27.0和19.6 nM以及19.9和14.5 nM。未发现FK143对两种同工酶的抑制活性在人和大鼠之间存在物种选择性。我们还研究了FK143对大鼠类固醇5α-还原酶同工酶编码基因的体内表达的影响。FK143减少了去势大鼠中睾酮诱导的1型mRNA量的增加，而对2型mRNA的量没有实质性影响。
