Weisser H, Krieg M
Institute of Clinical Chemistry, Transfusion and Laboratory Medicine, University Clinic Bergmannsheil, Bochum, Germany.
J Steroid Biochem Mol Biol. 1998 Oct;67(1):49-55. doi: 10.1016/s0960-0760(98)00071-5.
Finasteride is a well known steroid 5alpha-reductase inhibitor. In this context, recently we have shown that in human benign prostatic hyperplasia (BPH) finasteride inhibits the 5alpha-reduction of testosterone to dihydrostestosterone (DHT) more effectively in the epithelium as compared to the stroma. The aim of the present study was to describe in epithelium and stroma of human BPH the effect of finasteride on the 5alpha-reduction of androstenedione, that is the second main circulating androgen in men, to androstanedione. Using a finasteride concentration of 75 nM and an androstenedione concentration of 220 nM, the mean inhibition [% +/- SEM] of 5alpha-reductase activity was significantly higher in epithelium (69 +/- 2) than in stroma (52 +/- 4). Both in epithelium and stroma, this inhibition of 5alpha-reductase activity was dose-dependent and competitive. Dixon plots as well as slope replots of Lineweaver-Burk plots showed that the mean inhibition constant Ki (nM +/- SEM) was significantly lower in epithelium (10 +/- 1 and 11 +/- 2, respectively) than in stroma (33 +/- 7 and 28 +/- 4, respectively) indicating a significantly stronger inhibitory effect of finasteride in epithelium. From those mean Ki values, it follows that in human BPH finasteride inhibits equally well both the 5alpha-reduction of androstenedione to androstanedione and testosterone to DHT. Based on these inhibition studies, there is no evidence for the coexistence of substrate-specific 5alpha-reductases converting either testosterone or androstenedione. However, the striking difference in finasteride sensitivity of the 5alpha-reduction between epithelium and stroma could be due to a cell-type specific expression of structurally different 5alpha-reductases as well as to a different access of finasteride to 5alpha-reductase in epithelium and stroma where, compared to each other, the lipid environment is significantly different.
非那雄胺是一种著名的甾体5α-还原酶抑制剂。在此背景下，最近我们发现，在人类良性前列腺增生（BPH）中，与基质相比，非那雄胺在上皮细胞中更有效地抑制睾酮向双氢睾酮（DHT）的5α-还原。本研究的目的是描述在人类BPH的上皮细胞和基质中，非那雄胺对雄烯二酮（男性体内第二主要循环雄激素）向雄烷二酮的5α-还原的影响。使用75 nM的非那雄胺浓度和220 nM的雄烯二酮浓度，上皮细胞中5α-还原酶活性的平均抑制率[％±SEM]（69±2）显著高于基质（52±4）。在上皮细胞和基质中，这种对5α-还原酶活性的抑制均呈剂量依赖性且具有竞争性。Dixon图以及Lineweaver-Burk图的斜率重绘图显示，上皮细胞中的平均抑制常数Ki（nM±SEM）（分别为10±1和11±2）显著低于基质（分别为33±7和28±4），表明非那雄胺在上皮细胞中的抑制作用明显更强。从这些平均Ki值可以得出，在人类BPH中，非那雄胺对雄烯二酮向雄烷二酮的5α-还原以及睾酮向DHT的5α-还原的抑制效果相同。基于这些抑制研究，没有证据表明存在将睾酮或雄烯二酮转化的底物特异性5α-还原酶。然而，上皮细胞和基质之间5α-还原对非那雄胺敏感性的显著差异可能是由于结构不同的5α-还原酶的细胞类型特异性表达，以及非那雄胺在上皮细胞和基质中与5α-还原酶的不同接触，其中两者的脂质环境彼此相比存在显著差异。
