Imidazole antimycotics: inhibitors of steroid aromatase.
Imidazole antimycotics: inhibitors of steroid aromatase.
复制标题
咪唑类抗真菌药：类固醇芳香酶抑制剂。
DOI：
10.1016/0006-2952(85)90613-6
复制
发表时间：
1985
影响因子：
5.8
通讯作者：
Sheets,JJ
中科院分区：
文献类型：
--
作者：
Mason,JI;Murry,BA;Olcott,M;Sheets,JJ
咪康唑和克霉唑是一类具有广谱抗真菌活性的咪唑类药物，被证明是人胎盘微粒体类固醇芳香酶活性的有效抑制剂。咪康唑、克霉唑、酮康唑和氨基乙硫胺对芳香酶活性的抑制i50值分别为0.6、1.8、60和44 μM。最有效的化合物咪康唑对芳香化酶底物雄烯二酮表现出竞争动力学。在测定条件下，雄烯二酮的表观抑制常数（Ki）为55 nM，表观抑制常数（Ki）为220 nM。咪康唑对芳香酶活性的抑制通过稀释是可逆的。咪康唑对胎盘线粒体富集部分的胆固醇侧链裂解活性的抑制作用相对较差，而克霉唑和酮康唑均能显著抑制线粒体单加氧酶活性。分光光度法研究表明，咪康唑与胎盘微粒体芳香化酶复合物的细胞色素P-450组分结合，对nadph -细胞色素（P-450）还原酶活性的影响可以忽略不计。这些结果有力地支持咪康唑与人胎盘微粒体细胞色素P-450的高亲和力直接相互作用，导致芳香酶活性的抑制。
Miconazole and clotrimazole, members of a class of imidazole agents which have broad spectrum antimycotic activity, were shown to be potent inhibitors of steroid aromatase activity of human placental microsomes. The I50values for the inhibition of aromatase activity by miconazole, clotrimazole, ketoconazole, and aminoglutethimide were 0.6, 1.8, 60 and 44 μM respectively. The most effective compound, miconazole, exhibited competitive kinetics with respect to androstenedione, the aromatase substrate. The apparent inhibitory constant (Ki) was 55 nM, under assay conditions where the apparentKmfor androstenedione was 220 nM. The inhibition of aromatase activity by miconazole was shown to be reversible by dilution. Miconazole was a relatively poor inhibitor of the cholesterol side chain cleavage activity of a placental mitochondria-enriched fraction, while both clotrimazole and ketoconazole markedly inhibited this mitochondrial monooxygenase activity. Spectrophotometric studies revealed that miconazole bound to the cytochrome P-450 component of the placental microsomal aromatase complex and had negligible effect on NADPH-cytochromec(P-450) reductase activity. These results strongly support direct interaction of miconazole with microsomal cytochrome P-450 in human placental microsomes with high affinity resulting in the inhibition of aromatase activity.