Jiangsu Center of Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210038, China; Department of Pharmacology, School of Medicine, Yangzhou University, Yangzhou 225001, China.
Toxicology. 2010 Apr 30;271(1-2):57-63. doi: 10.1016/j.tox.2010.03.004. Epub 2010 Mar 17.
Triptolide, a major active component of Tripterygium wilfordii Hook F (TWHF), has multiple pharmacological activities. However, its clinical use is often limited by its severe toxicity. In the present study, we evaluated the oral toxicity of triptolide in Sprague-Dawley rats for 28 days at the dosages of 0, 200 and 400microg/kg/day, respectively. Significant difference in the toxicity of triptolide at 400microg/kg was found between different sexes. The triptolide-treated female rats showed many abnormalities, including anorexia, diarrhea, leanness, suppression of weight gain and food intake, fatty liver, splenomegaly and atrophy of ovaries. In contrast, no such abnormalities were observed in male rats except for the significant reproductive toxicity. Furthermore, the metabolism of triptolide in liver microsomes from both sexes was investigated by HPLC. A greater rate of triptolide metabolism was observed in male rat hepatic microsomes, suggesting that one of the cytochrome P450s (CYPs) responsible for triptolide metabolism is male-specific or predominant at least. The inhibition experiments with CYP inhibitors showed that CYP3A and CYP2B were mainly involved in the metabolism of triptolide. In addition, since CYP3A2 is a male-predominant form in rats, significant sex difference in the metabolism of triptolide disappeared in vitro after anti-rat CYP3A2 antibody pretreatment. Results suggested that CYP3A2 made an important contribution to the sex-related metabolism of triptolide, which may result in the sex differences in triptolide toxicity.
雷公藤红素是卫矛科植物雷公藤（Tripterygium wilfordii Hook F）的主要活性成分，具有多种药理活性。然而，其临床应用常受到严重毒性的限制。在本研究中，我们分别以 0、200 和 400μg/kg/天的剂量，在 Sprague-Dawley 大鼠中评价了雷公藤红素的口服毒性，为期 28 天。在 400μg/kg 剂量下，雷公藤红素的毒性在雌雄两性之间存在显著差异。雷公藤红素处理的雌性大鼠表现出多种异常，包括食欲不振、腹泻、消瘦、体重和采食量下降、脂肪肝、脾肿大和卵巢萎缩。相比之下，雄性大鼠除了生殖毒性显著外，没有观察到此类异常。此外，还通过 HPLC 研究了雌雄两性肝微粒体中雷公藤红素的代谢。雄性大鼠肝微粒体中雷公藤红素的代谢率更高，表明至少有一个负责雷公藤红素代谢的细胞色素 P450（CYP）是雄性特异性或主要存在的。用 CYP 抑制剂进行的抑制实验表明，CYP3A 和 CYP2B 主要参与了雷公藤红素的代谢。此外，由于 CYP3A2 在大鼠中是雄性优势形式，因此在用抗大鼠 CYP3A2 抗体预处理后，体外雷公藤红素代谢的性别差异消失。结果表明，CYP3A2 对雷公藤红素的性别相关代谢具有重要贡献，这可能导致雷公藤红素毒性的性别差异。
