Institute of Cardiovascular Disease, Institute of Cardiovascular Disease of Integrated Traditional Chinese Medicine and Western Medicine, Branch of National Clinical Research Center for Chinese Medicine Cardiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203, China.
J Ethnopharmacol. 2022 Jun 28;292:115224. doi: 10.1016/j.jep.2022.115224. Epub 2022 Mar 26.
Triptolide (TP) exhibits extensive pharmacological activity, but its hepatotoxicity and intestinal injury are significant and limit its clinical use.
To investigate the effect of gut microbiota disturbance after antibiotic pretreatment on TP-induced hepatotoxicity, intestinal injury and their mechanism.
We compared the characteristics of TP-induced hepatotoxicity and intestinal injury in mice with or without antibiotic pretreatment. The levels of cytokines in the serum, immunohistochemistry, and the pharmacokinetics of TP were determined.
Antibiotic pretreatment aggravates TP-induced hepatotoxicity and ileum/colon injury. TP induces hepatotoxicity in a dose-dependent manner after antibiotic pretreatment. Serum IL-1β and IL-6 levels were increased in mice given oral TP after antibiotic pretreatment. TP can increase the expression of NLRP3 inflammasome in hepatocytes, and Oral TP after antibiotic pretreatment can significantly enhance its expression, but NLRP3 inflammasome no significant change in colon and ileum. The pharmacokinetic characteristics of TP are altered significantly by antibiotic pretreatment, as shown by a 145.87% increase in C, a 155.11% increase in AUC, a 155.1% increase in relative bioavailability, and a 15.44% delay in MRT. Moreover, TP causes hepatotoxicity in a time-dependent manner.
Antibiotic pretreatment aggravates triptolide-induced hepatotoxicity and intestinal injury through elevated inflammatory response and promoted triptolide absorption.
雷公藤红素（TP）表现出广泛的药理活性，但它的肝毒性和肠道损伤是显著的，并限制了其临床应用。
研究抗生素预处理后肠道微生物群紊乱对 TP 诱导的肝毒性、肠道损伤及其机制的影响。
我们比较了抗生素预处理前后小鼠 TP 诱导的肝毒性和肠道损伤的特征。测定了血清中细胞因子的水平、免疫组织化学和 TP 的药代动力学。
抗生素预处理加重 TP 诱导的肝毒性和回肠/结肠损伤。抗生素预处理后，TP 呈剂量依赖性诱导肝毒性。抗生素预处理后口服 TP 的小鼠血清中 IL-1β 和 IL-6 水平升高。TP 可在肝细胞中诱导 NLRP3 炎性小体的表达，抗生素预处理后口服 TP 可显著增强其表达，但在结肠和回肠中 NLRP3 炎性小体无明显变化。抗生素预处理显著改变 TP 的药代动力学特征，C 增加 145.87%，AUC 增加 155.11%，相对生物利用度增加 155.1%，MRT 延迟 15.44%。此外，TP 呈时间依赖性诱导肝毒性。
抗生素预处理通过增加炎症反应和促进雷公藤红素吸收加重雷公藤红素诱导的肝毒性和肠道损伤。
