Greiner J W, Kramer R E, Jarrell J, Colby H D
J Pharmacol Exp Ther. 1976 Sep;198(3):709-15.
Spironolactone administration (50 mg/kg/day for 3 days) to make guinea pigs decreased cortisol production by adrenal slices in vitro. Adrenal microsomal and mitochondrial cytochrome P-450 levels were also decreased after treatment with spironolactone. The decline in adrenal cytochrome P-450 content was accompanied by decreases in microsomal 21-hydroxylase and mitochondrial cholesterol side-chain cleavage and 11beta-hydroxylase activities. Activities of other adrenal enzymes, such as delta4-hydrogenase and NADPH-cytochrome c reductase, were unaffected by spironolactone treatment. Cortisone administration to guinea pigs failed to mimic the effects of spironolactone on adrenal function, which indicates specificity of spironolactone action and excludes inhibition of adrenocorticotropin secretion as a mode of action. Addition of spironolactone to isolated adrenal mitochondria or microsomes produced type I spectral changes with spectral dissociation constants similar to those for endogenous steroid substrates. Spironolactone, in vitro, inhibited 11beta- but not 21-hydroxylase activity. The results indicate that spironolactone administration diminishes the activity of adrenal mitochondrial as well as microsomal cytochrome P-450-containing enzymes, resulting in a fall in corticosteroid output.
给豚鼠服用螺内酯（50毫克/千克/天，持续3天）可降低体外肾上腺切片的皮质醇生成。用螺内酯治疗后，肾上腺微粒体和线粒体细胞色素P - 450水平也降低。肾上腺细胞色素P - 450含量的下降伴随着微粒体21 - 羟化酶、线粒体胆固醇侧链裂解酶和11β - 羟化酶活性的降低。其他肾上腺酶的活性，如δ4 - 脱氢酶和NADPH - 细胞色素c还原酶，不受螺内酯治疗的影响。给豚鼠注射可的松未能模拟螺内酯对肾上腺功能的影响，这表明螺内酯作用的特异性，并排除了抑制促肾上腺皮质激素分泌作为一种作用方式。将螺内酯添加到分离的肾上腺线粒体或微粒体中会产生I型光谱变化，其光谱解离常数与内源性类固醇底物相似。在体外，螺内酯抑制11β - 羟化酶活性，但不抑制21 - 羟化酶活性。结果表明，服用螺内酯会降低肾上腺线粒体以及含微粒体细胞色素P - 450酶的活性，导致皮质类固醇产量下降。
