Abstract：
We performed a 28-day repeated-dose toxicity study of ketoconazole, a widely used an antimycotic drug, based on the draft protocol of the \"Enhanced OECD Test Guideline 407\" (Enhanced TG407) to investigate whether ketoconazole has endocrine-mediated properties according to this assay. Seven-week-old SD rats were administered with ketoconazole daily by oral gavage at doses of 0, 6.25, 25 or 100 mg kg(-1) day(-1) for at least 28 days. The ketoconazole-treated male rats showed reduction of epididymis and accessory sex organ weights, spermatid retention in the seminiferous tubules, decrease of testosterone and increases of estradiol, luteinizing hormone (LH) and follicular stimulating hormone (FSH). A prolongation of the estrous cycle and increases of estradiol, LH and FSH were observed in the treated female rats. Thyroxin and triiodothyronine were decreased and thyroid-stimulating hormone was increased in both sexes; however, there were no compound-related microscopic lesions in the thyroid gland or changes in the thyroid weight. The endocrine-related effects of ketoconazole could be detected by the parameters examined in the present study based on the Organization for Economic Cooperation and Development (OECD) protocol, suggesting that the Enhanced TG407 protocol should be a suitable screening test for detection of endocrine-mediated effects of chemicals.
摘要：
我们进行了28天的酮康唑重复剂量毒性研究，一种广泛使用的抗真菌药物，根据“增强的OECD测试指南407”（增强的TG407）的方案草案，根据该测定法调查酮康唑是否具有内分泌介导的特性。通过口服管饲法每天以0、6.25、25或100mgkg（-1）天（-1）的剂量给7周龄SD大鼠施用酮康唑，持续至少28天。酮康唑治疗的雄性大鼠表现出附睾和附属性器官重量的减少，精子细胞保留在生精小管中，睾酮的减少和雌二醇的增加，黄体生成素（LH）和卵泡刺激素（FSH）。发情周期的延长和雌二醇的增加，在处理的雌性大鼠中观察到LH和FSH。两种性别的甲状腺素和三碘甲状腺原氨酸均减少，促甲状腺激素增加；然而，甲状腺中没有化合物相关的显微镜下病变或甲状腺重量的变化.酮康唑的内分泌相关作用可以通过本研究中基于经济合作与发展组织（OECD）协议检查的参数来检测。这表明增强型TG407方案应该是检测化学物质内分泌介导效应的合适筛查试验。
