Yamada T, Nakamura J, Murakami M, Okuno Y, Hosokawa S, Matsuo M, Yamada H
Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd, Osaka, Japan.
Toxicol Appl Pharmacol. 1994 Nov;129(1):146-54. doi: 10.1006/taap.1994.1238.
Studies were performed to examine the mechanism by which testicular Leydig cell tumors are induced in rats by administration of the antimicrobial agent oxolinic acid (1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo-3-quinolinecarboxylic acid). In these studies, the effects of oxolinic acid on serum levels of luteinizing hormone (LH), testosterone, and prolactin and the binding of testosterone to prostatic androgen receptors were examined. In a long-term hormonal study, male Wistar rats were fed a diet containing oxolinic acid at 0, 100, 1000, or 3000 ppm for 104 weeks. A statistically significant increase in serum LH levels was observed at 1000 and 3000 ppm, but no dose of oxolinic acid had a significant effect on serum testosterone levels. Serum LH levels were no longer elevated above control levels within 2 weeks of cessation of the administration of oxolinic acid. Oxolinic acid was found to have no effect on the rate of clearance of exogenous LH from the circulation. Serum prolactin levels were decreased by the administration of oxolinic acid. The increase in serum LH induced by oxolinic acid was completely blocked by the intraperitoneal injection of the dopamine antagonist haloperidol (2 mg/kg). In addition, no significant affinity of oxolinic acid for androgen receptors was found in an in vitro study. These findings suggest that: (1) oxolinic acid induces Leydig cell tumors in rats by chronically stimulating the release of LH from the pituitary, (2) the mechanism of stimulating the release of LH involves facilitation of the dopaminergic systems in the hypothalamus-pituitary axis, and (3) oxolinic acid has no effect on androgen-mediated feedback inhibition.
开展了多项研究，以探究通过给予抗菌剂恶喹酸（1-乙基-1,4-二氢-6,7-亚甲基二氧基-4-氧代-3-喹啉羧酸）在大鼠中诱发睾丸间质细胞瘤的机制。在这些研究中，检测了恶喹酸对血清促黄体生成素（LH）、睾酮和催乳素水平以及睾酮与前列腺雄激素受体结合的影响。在一项长期激素研究中，给雄性Wistar大鼠喂食含0、100、1000或3000 ppm恶喹酸的饲料，持续104周。在1000 ppm和3000 ppm时观察到血清LH水平有统计学意义的升高，但恶喹酸的任何剂量对血清睾酮水平均无显著影响。在停止给予恶喹酸后2周内，血清LH水平不再高于对照水平。发现恶喹酸对外源性LH从循环中的清除率没有影响。给予恶喹酸会使血清催乳素水平降低。腹腔注射多巴胺拮抗剂氟哌啶醇（2 mg/kg）可完全阻断恶喹酸诱导的血清LH升高。此外，在一项体外研究中未发现恶喹酸对雄激素受体有显著亲和力。这些发现表明：（1）恶喹酸通过长期刺激垂体释放LH在大鼠中诱发间质细胞瘤；（2）刺激LH释放的机制涉及促进下丘脑-垂体轴中的多巴胺能系统；（3）恶喹酸对雄激素介导的反馈抑制没有影响。
