Oxidative Stress leads to Hepatocytotoxicity

Oxidative stress leads directly to hepatotoxicity through lipid peroxidation. Lipid peroxidation occurs when ROS scavenge electrons from poly-unsaturated fatty acids (PUFA), including membrane phospholipids. Lipid peroxidation occurs in three steps: initiation (in which the PUFA radical is produced), propagation (in which PUFA radicals react with molecular oxygen and a non-radical molecule to produce a lipid peroxide and lipid radical), and termination (in which two radicals combine to form a non-radical). Left unchecked, the propagation chain reaction is highly damaging to cellular membranes. Lipid peroxidation of mitochondrial membranes has been shown to result in both necrosis and apoptosis. The former occurs due to decreased mitochondrial membrane potential leading to decreased ATP production. The latter is a result of mitochondrial permeability transition (MPT). MPT is a process that can lead to necrosis or apoptosis. It is an important cell death mechanism because it is sensitive to redox conditions. Accumulation of ROS and depletion of glutathione trigger the mitogen activated protein kinase (MAPK) cascade (ASK1-->MKK4-->JNK), which recruits Bax to the outer mitochondrial membrane (Youle and Strasser 2008). Bax triggers the opening of mitochondrial permeability transition pore (MTP), through which cytochrome c is released, which triggers the caspase cascade and apoptosis. Alternatively, when the MTP opens across the inner and outer mitochondrial membranes, mitochondrial swelling and decoupling of oxidative phosphorylation (i.e., loss of ATP generation) leads to cell death by necrosis (Pessayre, et al. 2010, Rasola and Bernardi 2007).

In parallel, oxidative stress triggers cytotoxicity indirectly by modifying redox sensitive cellular molecules. Proteins with neighboring cysteine residues sense ROS through the oxidation of adjacent thiol groups (2SH, reduced; S=S, oxidized). Examples of this include: (1) the cellular anti-oxidant glutathione (GSH), which acts to ‘mop up’ ROS (GSH oxidized to GS=SG), and its depletion is associated with elevated cytotoxicity because ROS levels remain elevated or increase; (2) the cellular anti-oxidant thioredoxin, which inhibits the apoptosis signaling kinase 1 (Ask1) in its reduced form, but not in its oxidized form (Liu, et al. 2000, Saitoh, et al. 1998); and, (3) the mitochondrial permeability transition pore, which opens when oxidized (Petronilli, et al. 1994). Oxidative stress can also produce cell death through the production of oxidative damage to DNA, which can lead to apoptosis through p53 signalling.  Examples of types of oxidative DNA damage include: (Sharma, et al. 2012, Shukla, et al. 2013, Skipper, et al. 2016).

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