Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: Lessons learned from acetaminophen hepatotoxicity

Abstract

Hepatotoxicity is a serious problem during drug development and for the use of many established drugs. For example, acetaminophen overdose is currently the most frequent cause of acute liver failure in the United States and Great Britain. Evaluation of the mechanisms of drug-induced liver injury indicates that mitochondria are critical targets for drug toxicity, either directly or indirectly through formation of reactive metabolites. The consequence of these modifications is generally a mitochondrial oxidant stress and peroxynitrite formation, which leads to structural alterations of proteins and mitochondrial DNA and eventually to the opening of mitochondrial membrane permeability transition (MPT) pores. MPT pore formation results in collapse of the mitochondrial membrane potential and cessation of ATP synthesis. In addition, the release of intermembrane proteins such as apoptosis-inducing factor and endonuclease G and their translocation to the nucleus leads to nuclear DNA fragmentation. Together these events trigger necrotic cell death. Alternatively, release of cytochrome c and other pro-apoptotic factors from mitochondria can promote caspase activation and apoptotic cell death. Drug toxicity can also induce an inflammatory response with formation of reactive oxygen species by Kupffer cells and neutrophils. If not properly detoxified, these extracellularly generated oxidants can diffuse into hepatocytes and trigger mitochondrial dysfunction and oxidant stress, which then induces the MPT and necrotic cell death. This review addresses the formation of oxidants and the defense mechanisms available for the cells and applies this knowledge to better understand mechanisms of drug hepatotoxicity, especially acetaminophen-induced liver injury.

Mitochondria and aging: A role for the mitochondrial transition pore?

“…Two opening states of the pore have been distinguished, a permanent or long‐lasting state which is associated with cell death, and a transient opening state having a physiological role by providing a pathway to release ROS and calcium from mitochondria which is also regulated by CypD (Elrod et al., 2010; Hausenloy, Wynne, Duchen, & Yellon, 2004; Petronilli et al., 1999). The mPTP is now considered to be central in numerous conditions such as heart, brain, or liver ischemia–reperfusion (Friberg & Wieloch, 2002; Halestrap, 2010; Kim, He, Qian, & Lemasters, 2003; Morin, Hauet, Spedding, & Tillement, 2001; Rauen & de Groot, 2004), drug‐induced liver injury (Jaeschke, McGill, & Ramachandran, 2012), age‐related neurodegenerative diseases (Rao, Carlson, & Yan, 2014), and accumulating data imply the mPTP in organ dysfunction occurring during aging (Hepple, 2016; Rocha‐Rodrigues et al., 2013; Toman & Fiskum, 2011). Conversely, caloric restriction, which is a proven strategy to delay aging and age‐related disease (Balasubramanian, Howell, & Anderson, 2017), is associated with the inhibition of mPTP opening (Amigo, Menezes‐Filho, Luévano‐Martínez, Chausse, & Kowaltowski, 2017; Hofer et al., 2009; Kristal & Yu, 1998; Menezes‐Filho et al., 2017).…”

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…This is followed by profound mitochondrial dysfunction and ATP depletion, overproduction of ROS, c‐jun N‐terminal kinase (JNK) activation, and massive hepatocellular necrosis (Jaeschke et al. 2012; Michaut et al. 2014).…”

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

“…This suggests that cases associated with irreversible ALF and death show metabolically-induced liver injury and mitochondrial dysfunction while cases associated with recovery indicate metabolically-induced hypersensitivity reactions. Since mitochondrial oxidant stress is well known to trigger hepatocyte necrosis [3, 33, 163, 164], these organelles may also be critical cellular targets for AED-mediated hepatotoxicity.…”

“…As discussed, APAP hepatotoxicity involves mitochondrial dysfunction [163]. In order to evaluate if there is evidence for mitochondrial damage in humans after APAP overdose, plasma of these patients was analyzed for mtDNA and glutamate dehydrogenase (GLDH), which are both located in the mitochondrial matrix [164].…”