异烟肼致线粒体损伤引起药物性肝损伤研究进展

中国临床药理学与治疗学 ›› 2015, Vol. 20 ›› Issue (3): 356-360.

• 综述与讲座 • 上一篇

异烟肼致线粒体损伤引起药物性肝损伤研究进展

郭瑶雪^1,2,3, 邓晔^1,2,3, 李春^1,2,3, 贺蕾艳^1,2,3, 彭文兴^1,2

¹中南大学湘雅二医院药剂科,长沙 410011,湖南;
²中南大学临床药学研究所,长沙 410011,湖南;
³中南大学药学院,长沙 410013,湖南

收稿日期:2014-06-05 修回日期:2014-09-29 发布日期:2015-04-08
通讯作者: 彭文兴,男,博士,教授,主任药师,硕士研究生导师,主要从事药代动力学、药物相互作用以及临床药理学研究。Tel: 0731-85292219 E-mail: pwx.csu@163.com
作者简介:郭瑶雪,女,硕士在读,主要从事药代动力学、药物相互作用以及临床药学研究。Tel: 15116331525 E-mail: guoyaoxue0210@163.com

Mitochondria dysfunction is involved in the pathogenesis of isoniazid-induced hepatotoxicity

GUO Yao-xue^1,2,3, DENG Ye^1,2,3, LI Chun^1,2,3, HE Lei-yan^1,2,3, PENG Wen-xing^1,2

¹Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan,China;
²Institute of Clinical Pharmacy, Central South University, Changsha 410011, Hunan,China;
³School of Pharmaceutical Sciences of Central South University, Changsha 410013, Hunan,China

Received:2014-06-05 Revised:2014-09-29 Published:2015-04-08

摘要/Abstract

摘要： 近年国内外研究表明,线粒体功能异常是各种肝损伤(肝功能衰竭、肝硬化、脂肪肝等)发生的重要机制之一,而在药物性肝损伤发展过程中线粒体也起着重要作用。异烟肼是临床应用广泛、效果显著的抗结核药,但在治疗过程中常引起药物性肝损伤。在某种程度上妨碍了结核病的治疗。研究发现线粒体损伤是异烟肼肝损伤发生发展中关键一环,异烟肼及其毒性产物肼可通过激动氧化应激反应;抑制线粒体呼吸链中酶的活性;干扰细胞能量代谢及对线粒体膜产生攻击等方式使其功能异常,最终导致线粒体损伤,进而启动细胞凋亡程序。本文将对线粒体在异烟肼致药物性肝损伤中的作用进行综述,旨在从亚细胞水平解释异烟肼致肝毒性的机制,为阐明异烟肼的肝毒性提供更为有力的证据。

关键词: 异烟肼, 药物性肝损伤, 线粒体功能异常

Abstract: Emerging evidence shows mitochondria dysfunction is one of the mechanisms of various liver injury, such as liver failure, cirrhosis and adipose infiltration, especially drug induced liver injury (DILI). Isoniazid is widely used in anti-tuberculosis (anti-TB) treatment but well known for the apparent liver injury which sometimes limit the efficacy of anti-TB regimen. There is growing evidence that mitochondria dysfunction is critial in INH-induced DILI. INH and its toxic metabolites induced oxidant stress of mitochondria, inhibition of respiratory chain enzymes and impairment of energy homeostasis, disruption of mitochondria membrane, finally led to mitochondria dysfunction and triggered apoptosis. This review discusses this emerging new paradigms of INH-induced DILI and highlights recent insights of sub-cell level in the mechanisms, as well as points to the existing large gaps in our understanding of the pathogenesis.

Key words: isoniazid, drug induced liver injury, mitochondria dysfunction

中图分类号:

R969

郭瑶雪, 邓晔, 李春, 贺蕾艳, 彭文兴. 异烟肼致线粒体损伤引起药物性肝损伤研究进展[J]. 中国临床药理学与治疗学, 2015, 20(3): 356-360.

GUO Yao-xue, DENG Ye, LI Chun, HE Lei-yan, PENG Wen-xing. Mitochondria dysfunction is involved in the pathogenesis of isoniazid-induced hepatotoxicity[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2015, 20(3): 356-360.

参考文献

[1] Boelsterli UA, Lee KK. Mechanisms of isoniazid-induced idiosyncratic liver injury: emerging role of mitochondrial stress [J]. J Gastroen Hepatol, 2014, 29(4): 678-687.
[2] Metushi IG, Cai P, Zhu X, et al. A fresh look at the mechanism of isoniazid-induced hepatotoxicity [J]. Clin Pharmacol Ther, 2011, 89(6): 911-914.
[3] Verma S, Kaplowitz N. Chapter 27-hepatotoxicity of antitubercular drugs [M]//Kaplowitz N, Deleve LD. Drug-induced liver disease (Third Edition). Boston:Academic Press, 2013: 483-504.
[4] Preziosi P. Isoniazid: metabolic aspects and toxicological correlates [J]. Curr Drug Meab, 2007, 8(8): 839-851.
[5] Shu C, Lee C, Lee M, et al. Hepatotoxicity due to first-line anti-tuberculosis drugs: a five-year experience in a Taiwan medical centre [J]. Int J Tuberc Lung Dis, 2013, 17(7): 934-939.
[6] Björnsson ES, Bergmann OM, Björnsson HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland [J]. Gastroenterology, 2013, 144(7): 1419-1425. e3.
[7] Fountain FF, Tolley E, Chrisman CR, et al. Isoniazid hepatotoxicity associated with treatment of latent tuberculosis infection*: A 7-year evaluation from a public health tuberculosis clinic [J]. Chest, 2005, 128(1): 116-123.
[8] Yew WW, Leung CC. Antituberculosis drugs and hepatotoxicity [J]. Am J Resp Crit Care, 2007, 175(8): 858-859.
[9] Metushi IG, Nakagawa T, Uetrecht J. Direct oxidation and covalent binding of isoniazid to rodent liver and human hepatic microsomes: humans are more like mice than rats [J]. Chem Res Toxicol, 2012, 25(11): 2567-2576.
[10]Cheng J, Krausz KW, Li F, et al. CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid [J]. Toxicol Appl Pharm , 2013, 266(2): 245-253.
[11]Lee KK, Fujimoto K, Zhang C, et al. Isoniazid-induced cell death is precipitated by underlying mitochondrial complex I dysfunction in mouse hepatocytes [J]. Free Radical Bio Med, 2013, 65: 584-594.
[12]Schwab CE, Tuschl H. In vitro studies on the toxicity of isoniazid in different cell lines [J]. Hum Exp Toxicol, 2003, 22(11): 607-615.
[13]Boelsterli UA, Lee KK. Mechanisms of isoniazid-induced idiosyncratic liver injury: Emerging role of mitochondrial stress [J]. J Gastroen Hepatol, 2014, 29(4): 678-687.
[14]Mcgill MR, Sharpe MR, Williams CD, et al. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation [J]. J Clin Invest, 2012, 122(4): 1574-1583.
[15]Gao C, Ding Y, Zhong L, et al. Tacrine induces apoptosis through lysosome- and mitochondria-dependent pathway in HepG2 cells [J]. Toxicol In Vitro, 2014, 28(4): 667-674.
[16]Russmann S, Kullak-Ublick GA, Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity [J]. Curr Med Chem, 2009, 16(23): 3041-3053.
[17]Ramachandran A, Lebofsky M, Weinman SA, et al. The impact of partial manganese superoxide dismutase (SOD2)-deficiency on mitochondrial oxidant stress, DNA fragmentation and liver injury during acetaminophen hepatotoxicity [J]. Toxicol Appl Pharm, 2011, 251(3): 226-233.
[18]Shuhendler AJ, Pu K. Real-time imaging of oxidative and nitrosative stress in the liver of live animals for drug-toxicity testing [J]. Nat Biotechnol , 2014, 32(4): 373-380.
[19]Matsumura F. On the significance of the role of cellular stress response reactions in the toxic actions of dioxin [J]. Biochem Pharmacol, 2003, 66(4): 527-540.
[20]张炜. 抗结核药物致小鼠肝细胞线粒体损伤的研究[D].华北煤炭医学院, 2010.
[21]Li F, Miao Y, Zhang L, et al. Metabolomic analysis reveals novel isoniazid metabolites and hydrazones in human urine [J]. Drug Metab Pharmacok, 2011, 26(6): 569-576.
[22]廖艳, 彭双清, 颜贤忠, 等. 抗结核药物异烟肼肝毒性时效关系的代谢组学 [J]. 中国医学科学院学报, 2007,29(6): 730-737.
[23]刘艳,刘丹,朱翠明, 等. 抗结核治疗后脂肪肝形成的临床观察 [J]. 中国临床药理学与治疗学, 2013, 18(11): 1280-1283.
[24]Mahapatra S, Woolhiser LK, Lenaerts AJ, et al. A novel metabolite of antituberculosis therapy demonstrates host activation of isoniazid and formation of the isoniazid-NAD+ adduct [J]. Antimicrob Agentsch, 2012, 56(1): 28-35.
[25]Boelsterli UA, Lim PL. Mitochondrial abnormalities--a link to idiosyncratic drug hepatotoxicity? [J]. Toxicol Appl Pharm, 2007, 220(1): 92-107.
[26]Zhang F, Xu R, Zhao MJ. QSG-7701 human hepatocytes form polarized acini in three-dimensional culture [J]. J Cell Biochem, 2010, 110(5): 1175-1186.
[27]Chowdhury A, Santra A, Bhattacharjee K, et al. Mitochondrial oxidative stress and permeability transition in isoniazid and rifampicin induced liver injury in mice [J]. J Hepatol, 2006, 45(1): 117-126.
[28]王建刚, 王淑英, 赵建龙, 等. 利福平增加异烟肼肝毒性的机制探讨 [J]. 洛阳医专学报, 1999, 17(1): 11-13.
[29]Carvalho NR, da Rosa EF, da Silva MH, et al. New therapeutic approach: diphenyl diselenide reduces mitochondrial dysfunction in acetaminophen-induced acute liver failure [J]. PLoS One , 2013, 8(12): e81961.

异烟肼致线粒体损伤引起药物性肝损伤研究进展

Mitochondria dysfunction is involved in the pathogenesis of isoniazid-induced hepatotoxicity

PDF (PC)

可视化

被引次数

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 4

编辑推荐

Metrics

本文评价

[1]	宋如铮, 彭英, 王广基, 孙建国. 定量蛋白质组学常用研究技术及其在肝源性疾病发病机制中的应用进展[J]. 中国临床药理学与治疗学, 2021, 26(5): 570-578.
[2]	许丽娜, 李月, 彭金咏. microRNA与药物性肝损伤[J]. 中国临床药理学与治疗学, 2020, 25(7): 803-809.
[3]	李红丽，文丹丹，贝承丽，高利臣，彭喜旭. 专项整治前后结核患者肝损伤及药物使用费用对比分析[J]. 中国临床药理学与治疗学, 2019, 24(9): 1030-1036.
[4]	胡琴, 刘维, 邵宏. 药物性肝损伤的药物治疗研究进展[J]. 中国临床药理学与治疗学, 2016, 21(2): 231-236.