Mechanisms of isoniazid‐induced idiosyncratic liver injury: Emerging role of mitochondrial stress

Abstract

Idiosyncratic drug-induced liver injury (DILI) is a significant adverse effect of antitubercular therapy with isoniazid (INH). Although the drug has been used for many decades, the underlying mode of action (both patient-specific and drug-specific mechanisms) leading to DILI are poorly understood. Among the patient-specific determinants of susceptibility to INH-associated DILI, the importance of HLA genetic variants has been increasingly recognized, whereas the role of polymorphisms of drug-metabolizing enzymes (NAT2 and CYP2E1) has become less important and remains controversial. However, these polymorphisms are merely correlative, and other molecular determinants of susceptibility have remained largely unknown. Regarding the drug-specific mechanisms underlying INHinduced liver injury, novel concepts have been emerging. Among these are covalent protein adduct formation via novel reactive intermediates, leading to hapten formation and a potential immune response, and interference with endogenous metabolism. Furthermore, INH and/or INH metabolites (e.g. hydrazine) can cause mitochondrial injury, which can lead to mitochondrial oxidant stress and impairment of energy homeostasis. Recent studies have revealed that underlying impairment of complex I function can trigger massive hepatocellular injury induced by otherwise nontoxic concentrations of INH superimposed on these mitochondrial deficiencies. This review discusses these emerging new paradigms of INH-induced DILI and highlights recent insights into the mechanisms, as well as points to the existing large gaps in our understanding of the pathogenesis.

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

“…Increases in transaminase levels have long been considered the major signs of INH-induced hepatotoxicity, with up to 20% of patients usually suffering from elevated ALT levels (34); in contrast with those previous reports, we observed that either acute (1-week) or subchronic (2-week) administration of INH led to reductions in ALT, AST, and alkaline phosphatase (ALP). On the other hand, increased time exposure to INH (4 weeks) was characterized by significant and severe increases in transaminase levels (data not shown).…”

Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease

“…DILI caused by clinically used drugs, industrial solvents, and environmental agents represent another significant medical problem with acute fulminant liver failure and death (Boelsterli & Lee, 2014;Jaeschke et al, 2012;Xie et al, 2014;Yuan & Kaplowitz, 2013). APAP, isoniazid, halothane, isoflurane, troglitazone, CCL4, benzene, and bromodichloromethane can cause DILI.…”

“…In addition, it is known that there are relatively large individual variations in the rate of ethanol elimination, possibly due to genetic and environmental factors (Li, Yin, Crabb, O'Connor, & Ramchandani, 2001). Furthermore, the liver disease progression can be exacerbated or facilitated especially in the presence of other comorbidity risk factors (Lieber, 2004a), such as hepatitis B or C virus (Mueller, Millonig, & Seitz, 2009;Otani et al, 2005;Rigamonti et al, 2003;Szabo, Saha, & Bukong, 2015;Szabo et al, 2010;Zakhari, 2013), HIV (Fan, Joshi, Koval, & Guidot, 2011;Persidsky et al, 2011), obesity (Cederbaum, 2012a;Hart, Morrison, Batty, Mitchell, & Davey, 2010;Loomba et al, 2013Loomba et al, , 2010, diabetes (Hassan et al, 2002), smoking (Kuper et al, 2000;Purohit, Rapaka, Kwon, & Song, 2013;Salaspuro & Salaspuro, 2004), clinically used drugs (Boelsterli & Lee, 2014;McClain, Kromhout, Peterson, & Holtzman, 1980;Seeff, Cuccherini, Zimmerman, Adler, & Benjamin, 1986), or environmental contaminants such as benzene in gasoline (Kalf, Post, & Snyder, 1987). For instance, people who drink more than 60 g/day are more likely to develop fibrosis, cirrhosis, hepatocellular carcinoma, and ultimately liver failure (Lucey, Mathurin, & Morgan, 2009;.…”

Usefulness of <i>in vitro</i> combination assays of mitochondrial dysfunction and apoptosis for the estimation of potential risk of idiosyncratic drug induced liver injury

“…5 cytes can be used and many compounds can be assessed in a screening assay with small amounts of compound. It has been reported that idiosyncratic DILI is closely related to mitochondrial dysfunction (Wang, 2014;Dykens et al, 2008;Boelsterli and Lee, 2014) and apoptosis of the hepatocytes (Beggs et al, 2014). In the present study, in order to establish an in vitro assay for the estimation of the potential risk of the idiosyncratic DILI, we employed a combination assay of two endpoints, mitochondrial dysfunction and apoptosis, using cryopreserved human hepatocytes as a new approach.…”

“…Mitochondria play a crucial role in cell death (both necrosis and apoptosis) in the hepatocytes and are considered to be one of the main factors determining the idiosyncrasy of human liver (Boelsterli and Lim, 2007). Many drugs which cause idiosyncratic DILI can impair mitochondrial function as assessed experimentally (Wang, 2014;Dykens et al, 2008;Boelsterli and Lee, 2014). Mitochondrial dysfunction includes uncoupling of oxidative phosphorylation, inhibition of complex I/III, an increase in mitochondrial oxidant stress, an increase in cellular calcium ion and activation of c-Jun N-terminal kinase (JNK), some of which induce apoptosis (Armstrong, 2006).…”