利托那韦对菊三七致大鼠肝毒性的保护作用  

The protective effect of ritonavir against Gynura japonica-induced liver injury in rats

作　　者：陈岩 叶铉玲 王汛江 杨莉[1,2] 熊爱珍 王长虹[1] 王峥涛 CHEN Yan;YE Xuan-ling;WANG Xun-jiang;YANG Li;XIONGAi-zhen;WANG Chang-hong;WANG Zheng-tao(The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines,Institute of Chinese Materia Medica,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China;Shanghai R&D Center for Standardization of Traditional Chinese Medicines,Shanghai 201203,China)

机构地区：[1]上海中医药大学,中药研究所,中药标准化教育部重点实验室暨国家中医药管理局中药新资源与质量评价重点实验室,上海201203 [2]上海中药标准化研究中心,上海201203

出　　处：《药学学报》2022年第2期392-398,共7页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81603384);上海市自然科学基金资助项目(20ZR1473300);上海市进一步加快中医药事业发展三年行动计划(ZY(2018-2020)-CCCX-5002);上海市人才发展资金(2020099);上海中医药大学“杏林学者”计划(B1-GY21-409-04-06)。

摘　　要：大量体外研究表明,吡咯里西啶生物碱(pyrrolizidine alkaloids,PAs)肝毒性与细胞色素酶P450(cytochrome P450,CYP)3A4密切相关,但尚未在整体水平得到证实。因此,本研究利用大鼠探讨CYP3A4化学抑制剂利托那韦对菊三七致肝损伤的影响。实验方案经上海中医药大学实验动物福利与伦理委员会审查,符合实验动物福利与伦理相关规范。大鼠单次灌胃菊三七提取物(8 g·kg^(-1))造成肝损伤模型,并设利托那韦(30 mg·kg^(-1))干预组、溶剂对照组和利托那韦对照组。结果表明,利托那韦对菊三七致大鼠肝损伤有明显的保护作用:利托那韦可明显降低肝损伤大鼠血清转氨酶活性及总胆汁酸水平,肝窦淤血、肝组织坏死等病理状态均有所缓解。进一步测定菊三七提取物给药后10 min~24 h内PAs致肝毒性生物标识物吡咯-蛋白结合物含量及主要胆汁酸的含量,发现利托那韦可明显降低血清吡咯-蛋白结合物含量,修复胆汁酸代谢紊乱。本研究表明,利托那韦可明显改善菊三七致大鼠肝损伤的情况,与抑制PAs代谢活化及调节胆汁酸代谢密切相关。研究结果加强了对CYP3A4酶与PAs毒性的相关性的理解,对于PAs临床疾病干预策略的开发以及含PAs药物临床用药安全的合理评估均具有重要意义。Numerous in vitro studies have shown that most pyrrolizidine alkaloids(PAs)are hepatotoxic after being metabolically activated by cytochrome P450(CYP)3A4.However,the key role of CYP3A4 has not been confirmed in vivo.Therefore,the CYP3A4 chemical inhibitor ritonavir was employed in this work and the effect of ritonavir on Gynura japonica-induced liver injury in rats was investigated.All experiments were approved by the Animal Research Committee of Shanghai University of Traditional Chinese Medicine.Animal welfare and the animal experimental protocols were strictly consistent with related ethics regulations of Shanghai University of Traditional Chinese Medicine.Acute liver injury was induced by a single gavage of Gynura japonica extracts(GJE,8 g·kg^(-1));rats in the protection group were gavaged with ritonavir(RIT,30 mg·kg^(-1))1 h before GJE treatment.The results show that RIT could significantly attenuate GJE-induced liver injury in rats.Rats in the protection group showed decreased serum activities for alanine aminotransferase and aspartate aminotransferase,as well as lower total bile acids.In addition,the infiltration of inflammatory cells,sinusoidal hemorrhage,and hepatic necrosis in GJE-treated rats were markedly attenuated in the protection group.The content of pyrrole-protein adducts(PPAs),a recommended biomarker for PA-induced hepatotoxicity in clinics,was determined at 10 min to 24 h after GJE treatment.The content of 13 bile acids was also quantified.RIT treatment reduced the content of PPAs in serum dramatically and restored the impaired bile acid homeostasis caused by GJE.These studies indicate that RIT attenuated Gynura japonica-induced liver injury in rats,which was closely related to the inhibition of the metabolic activation of PAs and the regulation of bile acid metabolism.These results provide a better understanding of the relationship between CYP3A4 and PA-induced toxicity.This work will also be helpful in developing effective treatments for PA-induced liver injury and making a reasonable eval

关 键 词：吡咯里西啶生物碱 代谢活化 胆汁酸 CYP3A4 利托那韦 肝毒性 

分 类 号：R963[医药卫生—微生物与生化药学]