Buttke T M, Chapman S W
Antimicrob Agents Chemother. 1983 Oct;24(4):478-85. doi: 10.1128/AAC.24.4.478.
The effects of ketoconazole on mitogen-induced DNA synthesis and cholesterol biosynthesis in human and murine lymphocytes have been examined. Ketoconazole concentrations which do not affect cell viability (0.1 to 10 micrograms/ml) in culture led to a dose-dependent inhibition of DNA synthesis, as measured by [3H]thymidine incorporation, induced by either T-cell or B-cell mitogens. At drug concentrations 5- to 10-fold lower, ketoconazole inhibited the incorporation of [14C]acetate into cholesterol, with a resultant accumulation of [14C]lanosterol. The suppressive effects of ketoconazole on DNA synthesis were reversed by increasing the concentration of human serum in the culture medium from 5 to 20%. The depletion of lipoproteins in human serum by density centrifugation reduced the cholesterol content by 90% but did not affect the ability of the serum to overcome the inhibition by ketoconazole of DNA synthesis. Unlike DNA synthesis, cholesterol biosynthesis was not restored by 20% fresh human serum or lipoprotein-depleted human serum. These results demonstrate that ketoconazole potently inhibits DNA synthesis and cholesterol synthesis in mitogen-stimulated lymphocytes at drug concentrations obtained therapeutically. Further, the uncoupling of endogenous cholesterol synthesis and DNA synthesis indicates at least two levels of action of ketoconazole in mammalian lymphocytes.
已研究了酮康唑对人及小鼠淋巴细胞中丝裂原诱导的DNA合成和胆固醇生物合成的影响。在培养中不影响细胞活力（0.1至10微克/毫升）的酮康唑浓度导致DNA合成呈剂量依赖性抑制，这通过[3H]胸苷掺入法来测量，该抑制由T细胞或B细胞丝裂原诱导。在药物浓度低5至10倍时，酮康唑抑制[14C]乙酸盐掺入胆固醇，导致[14C]羊毛甾醇积累。通过将培养基中人类血清的浓度从5%提高到20%，酮康唑对DNA合成的抑制作用得以逆转。通过密度离心法去除人血清中的脂蛋白可使胆固醇含量降低90%，但不影响血清克服酮康唑对DNA合成抑制的能力。与DNA合成不同，20%的新鲜人血清或去除脂蛋白的人血清不能恢复胆固醇生物合成。这些结果表明，在治疗所达到的药物浓度下，酮康唑能有效抑制丝裂原刺激的淋巴细胞中的DNA合成和胆固醇合成。此外，内源性胆固醇合成与DNA合成的解偶联表明酮康唑在哺乳动物淋巴细胞中至少有两个作用水平。
