Hepatotoxicity mechanisms of isoniazid: A mini-review Hozeifa M. Hassan a,f , Hong-li Guo a , Bashir A. Yousef a,g , Zhang Luyong a,b,d * and Jiang Zhenzhou a,c,e * ABSTRACT: Isoniazid (INH) is an antituberculosis drug associated with idiosyncratic liver injury in susceptible patients. INH-induced hepatotoxicity remains a significant clinical problem, but the underlying mechanisms are still unclear, despite the growing evidence that INH and/or its major metabolite, hydrazine, play an important role in hepatotoxicity. Copyright © 2015 John Wiley & Sons, Ltd. Keywords: isoniazid; hepatotoxicity mechanisms; CYP2E1 Introduction Tuberculosis (TB) remains a major global health problem, whose effects have major impact in developing countries, despite the availability of highly efficacious treatment for decades (Lyoumi et al., 2013; Ramappa and Aithal, 2013; Singh et al., 2014). World Health Organization (WHO) declared TB a global public health emergency in 1993 (Ramappa and Aithal, 2013). Recommended standard treatment for adult respiratory TB is a regimen of isonia- zid (INH), rifampicin and pyrazinamide for 2 months, followed by 4 months of INH and rifampicin. Ethambutol is usually added to this regimen and streptomycin is recommended by the WHO in retreatment cases in most developing countries (Sharifzadeh et al., 2005; Tostmann et al., 2008a). The most frequent adverse effect of anti-TB treatment is hepatotoxicity (Obogwu et al., 2014; Park et al., 2010; Sharifzadeh et al., 2005; Sharma, 2004; Shih et al ., 2013; Tostmann et al., 2008a). Anti-TB drug-induced hepatotoxicity is a serious problem and main cause of treatment interruption and change in treatment regimen during the TB treatment course (Khalili et al., 2009; Tostmann et al., 2008b). Anti-TB drug-induced hepatotoxicity causes substantial morbidity and mortality. Asymptomatic trans- aminase elevations are common during anti-TB treatment, but hepatotoxicity can be fatal when not recognized early and when therapy is not interrupted in time. Anti-TB drugs such as INH, rifam- picin and pyrazinamide have been found to be potentially hepato- toxic (Park et al., 2010; Sharifzadeh et al., 2005). There has been a report of ethambutol-induced liver cholestatic jaundice, with un- clear circumstances. The risk of anti-TB drug-induced hepatotoxi- city has been found to increase by various factors such as high alcohol intake, older age, pre-existing chronic liver disease, chronic viral infection, advanced TB, female sex, concomitant administra- tion of hepatotoxic drugs, inappropriate use of drugs and nutritional status (Hosford et al., 2015; Khalili et al., 2009; Sharma, 2004; Uetrecht and Naisbitt, 2013). INH is a first-line medication used in the treatment of TB. How- ever, INH therapy is associated with serious hepatotoxicity and potentially fatal liver injury (Georgieva et al., 2005; Metushi and Uetrecht, 2014b; Sarich et al., 1995 Tafazoli et al., 2008). Therefore, the purpose of this review is to understand the possible mecha- nisms by which INH causes hepatotoxicity. Hepatotoxicity of isoniazid INH is a widely used first-line anti-TB drug that has been associated with idiosyncratic (host-dependent) drug-induced liver injury in susceptible patients. The incidence of INH-related hepatic adverse reactions is relatively high, as compared to that induced by other drugs (Lee et al ., 2013). The use of INH is associated with elevated serum levels of alanine aminotransferase in up to 20% of patients, whereas overt hepatotoxicity can occur in up to 2% of patients (Boelsterli and Lee, 2014; CDC, 2010; Metushi et al., 2011; Walubo et al ., 1998). Although the pathology can vary, in most cases liver biopsies from patients with severe hepatotoxicity are indistin- guishable from those from patients with viral hepatitis; the find- ings include necrosis, inflammation and, in some instances, an *Correspondence to: Zhang Luyong or Jiang Zhenzhou, Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China. E-mail: lyzhang@cpu.edu.cn; beaglejiang@cpu.edu.cn a Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China b Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharma- ceutical University, Nanjing, China c Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharma- ceutical University), Ministry of Education, Nanjing, China d Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, China e State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China f Department of Pharmacology, Faculty of Pharmacy, University of Gezira, Wad-Medani, Sudan g Department of Pharmacology, Faculty of Pharmacy, University of Khartoum, Khartoum, Sudan J. Appl. Toxicol. 2015; 35: 1427–1432 Copyright © 2015 John Wiley & Sons, Ltd. Review article Received: 15 April 2015, Accepted: 17 April 2015 Published online in Wiley Online Library: 10 June 2015 (wileyonlinelibrary.com) DOI 10.1002/jat.3175 1427