Doody K M, Murry B A, Mason J I
Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas 75235.
J Enzyme Inhib. 1990;4(2):153-8. doi: 10.3109/14756369009040737.
The efficacies of 10-propargylestr-4-ene-3,17-dione (PED), 4-hydroxyandrostenedione (4-OHA) and the imidazole broad spectrum antimycotic drugs, econazole, imazalil, miconazole and ketoconazole, to inhibit the steroid aromatase activities of rat Leydig tumor (R2C) cells and human hepatoma (HEPG2) cells have been determined. The analysis of inhibition of steroid aromatase activity of intact cells provided further insight into the potential use of such drugs to block cellular estrogen synthesis. The IC50 values for the inhibition of aromatase activity of R2C cells by econazole, imazalil, miconazole, ketoconazole, 4-OHA and PED were 4, 9, 40, 1100, 11 and 10 nM, respectively. These drugs also inhibited the steroid aromatase activity of HEPG2 cells with corresponding IC50 values of 13, 27, 20, 15000, 2 and 2 nM, respectively; these findings were suggestive that the steroid aromatase of rat has many similarities to the human enzyme in its interaction with putative inhibitory compounds. Importantly, however, ketoconazole inhibited the rat aromatase more effectively than it did the human enzyme, while PED and 4-OHA were less effective inhibitors of the rat enzyme compared to that of human. These findings indicate differences in the potencies of various drugs to inhibit estrogen biosynthesis in human and rat cells. These may relate to differences in the two aromatase systems and/or differences in the stability of the drugs in the human hepatoma and rat Leydig tumor cells.
已测定了10-炔丙基雌甾-4-烯-3,17-二酮（PED）、4-羟基雄烯二酮（4-OHA）以及咪唑类广谱抗真菌药物益康唑、抑霉唑、咪康唑和酮康唑对大鼠睾丸间质细胞瘤（R2C）细胞和人肝癌（HEPG2）细胞甾体芳香化酶活性的抑制效果。对完整细胞甾体芳香化酶活性抑制情况的分析，进一步深入了解了此类药物在阻断细胞雌激素合成方面的潜在用途。益康唑、抑霉唑、咪康唑、酮康唑、4-OHA和PED对R2C细胞芳香化酶活性抑制的IC50值分别为4、9、40、1100、11和10 nM。这些药物也抑制了HEPG2细胞的甾体芳香化酶活性，相应的IC50值分别为13、27、20、15000、2和2 nM；这些结果表明，大鼠的甾体芳香化酶在与假定的抑制性化合物相互作用方面与人类酶有许多相似之处。然而，重要的是，酮康唑对大鼠芳香化酶的抑制作用比对人类酶更有效，而PED和4-OHA对大鼠酶的抑制作用比对人类酶的抑制作用弱。这些发现表明，各种药物在抑制人和大鼠细胞中雌激素生物合成的效力上存在差异。这可能与两种芳香化酶系统的差异和/或药物在人肝癌细胞和大鼠睾丸间质细胞瘤细胞中的稳定性差异有关。
