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

Abstract

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

CLC Number:

R969

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.

References

[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.