摘要
环磷酰胺(cyclophosphamide,CPA)是治疗多种肿瘤的一线化疗药,但过量应用可引起肝损伤。本文旨在探讨氧化苦参碱(oxymatrine,OMT)与CPA的联合给药是否会加剧其肝毒性,并初步阐明其机制。小鼠单独给药OMT(100 mg·kg^-1)不同时间后,检测肝组织Cyp2b10 mRNA和CYP2B10蛋白表达。小鼠灌胃(intragastric adminis‐tration,ig)给药不同剂量OMT,同时隔天腹腔注射(intraperitoneal injection,ip)给予CPA(200 mg·kg^-1),10天后,检测血清谷丙/谷草转氨酶(alanine/aspartate aminotransferase,ALT/AST)活力,记录小鼠死亡率,检测肝组织Cyp2b10mRNA水平,并分析ALT/AST活力、死亡率和Cyp2b10 mRNA水平间的相关性。本文中动物福利和实验过程均遵循上海中医药大学实验动物伦理委员会的规定。结果发现,OMT单独给药可以显著提高小鼠肝组织中Cyp2b10mRNA和CYP2B10蛋白表达(P<0.05),并增强其酶活性(P<0.05)。OMT与CPA联合给药后,可明显提高CPA引起的小鼠死亡率(33.3%→58.3%);血清生化指标分析以及肝组织Cyp2b10 mRNA水平分析结果显示,OMT可进一步提高CPA诱导的小鼠血清ALT和AST活力以及肝组织Cyp2b10 mRNA水平(P<0.05)。血清ALT/AST活力与小鼠死亡率和肝组织Cyp2b10 mRNA水平之间均有良好的相关性。以上结果说明,OMT可以通过诱导小鼠肝组织Cyp2b10 mRNA表达,提升CYP2B10酶活性,促进CPA在肝脏代谢,从而加剧其诱导的肝毒性。
Cyclophosphamide(CPA)is the first-line chemotherapy for many tumors,but its overdose will lead to hepatotoxicity.This study aims to investigate whether the combined administration of oxymatrine(OMT)with CPA will aggravate the hepatotoxicity induced by CPA and its engaged mechanism.The expression of hepatic Cyp2b10 mRNA and CYP2B10 protein was detected by qPCR and Western blot in mice at different times after OMT(100 mg·kg^-1)administration.Mice were given with different doses of OMT(intragastric administration,ig)every day.At the same time,CPA(200 mg·kg^-1)was also intraperitoneally injected into mice every other day.After10 days,serum alanine/aspartate aminotransferase(ALT/AST)activity,the mortality of mice and hepatic mRNA expression of Cyp2b10 were detected.Furthermore,the correlation among ALT/AST activity,the mortality and Cyp2b10 mRNA expression was analyzed.All animals were received humane care according to the institutional animal care guidelines approved by the Experimental Animal Ethical Committee of Shanghai University of Traditional Chinese Medicine.The results showed that OMT itself enhanced hepatic mRNA and protein expression of Cyp2b10(P<0.05),and increased liver enzymatic activity of CYP2B10 in mice(P<0.05).In mice treated with CPA plus OMT,OMT obviously enhanced the mortality of mice induced by CPA(from 33.3%to 58.3%).The results of serum biochemical analysis and hepatic mRNA expression of Cyp2b10 showed that OMT further enhanced the increased serum ALT/AST activity and hepatic Cyp2b10 mRNA expression in mice(P<0.05).There was a good correlation between serum ALT/AST activity and mortality or hepatic Cyp2b10 mRNA expression.These results showed that OMT could enhance hepatic Cyp2b10 mRNA expression and increase liver CYP2B10 enzymatic activity,and then promoted the metabolism of CPA,and thus aggravated CPA-induced hepatotoxicity in mice.
作者
赵青
黄镇林
卫梦娟
管辉达
张少波
陆宾
季莉莉
ZHAO Qing;HUANG Zhen-lin;WEI Meng-juan;GUAN Hui-da;ZHANG Shao-bo;LU Bin;JI Li-li(The MOE Key Laboratory for Standardization of Chinese Medicines,Shanghai Key Laboratory for Compound Chinese Medicines,Institute of Chinese Materia Medica,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China)
出处
《药学学报》
CAS
CSCD
北大核心
2020年第6期1193-1200,共8页
Acta Pharmaceutica Sinica
基金
国家“重大新药创制”科技重大专项(2015ZX09501004-002-002)
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)。
