Ni Bin, Jiang Zhenzhou, Huang Xin, Xu Fengguo, Zhang Rui, Zhang Zunjian, Tian Yuan, Wang Tao, Zhu Tian, Liu Jing, Zhang Luyong
National Drug Screening Center, China Pharmaceutical University, Nanjing, The People's Republic of China.
Arzneimittelforschung. 2008;58(12):673-80. doi: 10.1055/s-0031-1296570.
As the unique quality control standard of Tabellae Glucosidorum Tripterygii Totorum, triptolide (CAS 38748-32-2) has a narrow therapeutic window. A significant side-effect of triptolide is its male reproductive toxicity the mechanism of which is still unknown. Therefore, in the present study the male reproductive toxicity and toxicokinetics of triptolide were investigated. Male Sprague-Dawley (SD) rats were treated with triptolide by oral administration (gastric infusion; 0, 100, 200, 400 microg/kg) once daily for 8 weeks. At the end of the treatment, the concentrations of triptolide in blood and testis samples were analyzed with liquid chromatography/mass spectrometry (LC/MS) to obtain the toxicokinetic parameters. Triptolide showed a non-linear kinetics profile and was rapidly absorbed but relatively slowly eliminated in the rats. Specifically, an accumulation of triptolide was seen in the testis. In the hematological study, mean corpuscular hemoglobin concentration (MCHC) had a marginal decrease in all triptolide treated groups. Alkaline phosphatase (ALP) in serum increased significantly only in the 400 microg/kg group during clinical chemistry assays although no histopathological change was found in the hematopoietic system or liver. In the male reproductive toxicity studies, the testis and epididymis weights of all triptolide treatment groups decreased significantly. The cauda epididymis sperm content and motility even decreased to zero. Evident changes were observed in the seminiferous tubules and the epididymides of triptolide treated rats (e.g., intraepithelial vacuoles of varying sizes; increased germ cells de generation, exfoliation and tubular atrophy). These findings provide valuable information to estimate the reproductive risk of triptolide in humans.
雷公藤甲素（CAS 38748-32-2）作为雷公藤多苷片独特的质量控制标准，其治疗窗较窄。雷公藤甲素的一个显著副作用是其雄性生殖毒性，其机制尚不清楚。因此，在本研究中，对雷公藤甲素的雄性生殖毒性和毒代动力学进行了研究。雄性Sprague-Dawley（SD）大鼠每天经口给予雷公藤甲素（灌胃；0、100、200、400微克/千克），连续8周。治疗结束时，采用液相色谱/质谱联用（LC/MS）分析血液和睾丸样本中雷公藤甲素的浓度，以获得毒代动力学参数。雷公藤甲素在大鼠体内呈现非线性动力学特征，吸收迅速但消除相对缓慢。具体而言，在睾丸中观察到雷公藤甲素的蓄积。在血液学研究中，所有雷公藤甲素治疗组的平均红细胞血红蛋白浓度（MCHC）均略有下降。临床化学检测中，仅400微克/千克组的血清碱性磷酸酶（ALP）显著升高，尽管在造血系统或肝脏中未发现组织病理学变化。在雄性生殖毒性研究中，所有雷公藤甲素治疗组的睾丸和附睾重量均显著下降。附睾尾部精子含量和活力甚至降至零。在雷公藤甲素处理的大鼠的生精小管和附睾中观察到明显变化（例如，大小不一的上皮内空泡；生殖细胞退变、脱落增加和小管萎缩）。这些发现为评估雷公藤甲素对人类的生殖风险提供了有价值的信息。
