马兜铃酸I对小鼠肝脏代谢酶的影响研究

doi:10.19803/j.1672-8629.2020.07.05

中国药物警戒 ›› 2020, Vol. 17 ›› Issue (7): 403-407.
DOI: 10.19803/j.1672-8629.2020.07.05

马兜铃酸I对小鼠肝脏代谢酶的影响研究

姬海南¹, 李海山¹, 宋乃宁¹, 李斌², 隋峰³, 李鹰飞³, 郭家彬⁴, 贾强⁵, 李桦⁶, 高月⁷, 沈国林^1,*

¹中国检验检疫科学研究院化学品安全研究所,北京 100123;
²中国疾病预防控制中心职业卫生与中毒控制所,北京 100050;
³中国中医科学院中药研究所,北京 100170;
⁴中国人民解放军疾病预防控制中心,北京 100071;
⁵山东省职业卫生与职业病防治研究院,山东济南 250062;
⁶军事科学院军事医学研究院毒物药物研究所,北京 100850;
⁷军事科学院军事医学研究院辐射医学研究所,北京 100850

收稿日期:2019-04-02 修回日期:2020-06-22 出版日期:2020-07-15 发布日期:2020-06-22
通讯作者: ^*沈国林,男,博士,副研究员,化学品安全。E-mail：shengl@aqsiqch.ac.cn
作者简介:姬海南,男,助理研究员,化学品安全。
基金资助:
公益性科研院所基本科研业务费专项资金资助项目：马兜铃酸I对肝脏代谢功能影响和肾脏毒性与肠道菌群的相关性研究（2019JK038）; 化学品毒性评价新模型的建立及其应用研究（2018JK021）; 基于毒性整体早期评价的典型高关注化学物质肝毒性生物标志物筛选关键技术研究（2017JK042）; 国家重点研发计划：化学品健康危害快速分级与确证技术研究（2017YFF0211201）

Effect of Aristolochic Acid I on Liver Metabolic Enzymes of Mice

JI Hainan¹, LI Haishan¹, SONG Naining¹, LI Bin², SUI Feng³, LI Yingfei³, GUO Jiabin⁴, JIA Qiang⁵, LI Hua⁶, GAO Yue⁷, SHEN Guolin^1,*

¹Institute of Chemicals Safety,Chinese Academy of Inspection and Quarantine, Beijing 100123, China;
²The National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050,China;
³Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100170,China;
⁴Center of Disease Control and Prevention, PLA, Beijing 100071, China;
⁵Shandong Academy of Occupational Health and Occupational Medicine, Jinan Shandong 250062, China;
⁶Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China;
⁷Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing 100850, China

Received:2019-04-02 Revised:2020-06-22 Online:2020-07-15 Published:2020-06-22

摘要/Abstract

摘要： 目的利用代谢动力学等相关技术研究马兜铃酸I对小鼠肝脏代谢酶的影响,揭示马兜铃酸I影响小鼠肝脏代谢功能的作用机制。方法取雄性6周龄C57BL/6 小鼠作为研究对象,按照设定的马兜铃酸I剂量随机分为4个给药组和l个正常对照组,灌胃给药,每周5天,连续4周,利用代谢动力学相关技术和分子生物学手段研究马兜铃酸I对小鼠肝脏代谢酶的影响。结果显示马兜铃酸I可以诱导小鼠肝脏细胞色素P4501a2和细胞色素P4503a11的酶活性和mRNA表达,也可以通过诱导磺基转移酶增加吲哚酚硫酸的含量,但不是主要因素。AAI引起的肾毒性是吲哚酚硫酸在血浆、肝脏和肾脏蓄积的主要原因,反过来也加重了AAI引起的肾脏毒性。结论马兜铃酸I对小鼠肝脏代谢酶有多重影响。

关键词: 马兜铃酸I, CYP450酶, 胆汁酸合成酶, 磺基转移酶, 分子对接

Abstract: Objective To determine the effect of aristolochic acid I (AAI) on the liver metabolic enzymes of mice and the associated mechanism using metabolic kinetics and related techniques. Methods Male 6-week-old C57BL/6 mice were assigned to four treatment groups and one control group. Established doses of AAI (0.2, 2, 10, and 20 mg/kg) were administered intragastrically 5 days per week for 4 weeks. The effects of AAI on liver metabolic enzymes were determined using metabolic kinetics and molecular biology techniques. Results AAI induced enzyme activities and mRNA expressions of liver cyp1a2 and cyp3a11, and increased the content of indoxylsulfuric acid by inducing sulfotransferase (SULT1B1). However, renal toxicity induced by AAI was the main cause of the accumulation of indoxylsulfuric acid in the plasma, liver, and kidney, which in turn aggravated the renal toxicity caused by AAI. Conclusion AAI has multiple effects on liver metabolic enzymes in mice.

Key words: aristolochic acid I, CYP450 enzyme, bile acid synthetase, sulfotransferase, molecular docking

中图分类号:

R994.11

姬海南, 李海山, 宋乃宁, 李斌, 隋峰, 李鹰飞, 郭家彬, 贾强, 李桦, 高月, 沈国林. 马兜铃酸I对小鼠肝脏代谢酶的影响研究[J]. 中国药物警戒, 2020, 17(7): 403-407.

JI Hainan, LI Haishan, SONG Naining, LI Bin, SUI Feng, LI Yingfei, GUO Jiabin, JIA Qiang, LI Hua, GAO Yue, SHEN Guolin. Effect of Aristolochic Acid I on Liver Metabolic Enzymes of Mice[J]. Chinese Journal of Pharmacovigilance, 2020, 17(7): 403-407.

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马兜铃酸I对小鼠肝脏代谢酶的影响研究

Effect of Aristolochic Acid I on Liver Metabolic Enzymes of Mice

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