2 Rechallenge events commonly result in jaundice (64%), hospitalization (52%), or allergic/hypersensitivity features (39%).4 Most rechallenge events are inadvertent and hence preventable if initial DILI is accurately identified and clearly communicated to the patient. DILI results from the cumulative effects of oxidative stress, reactive metabolites,

immune injury from protein adducts, inhibition or disruption of transporters or drug metabolism, mitochondrial impairment,8 loss of ion gradients and adenosine triphosphate (ATP), and activation of programmed cell death or necrosis.9 Intraindividual and environmental factors, inflammatory mediators, and glutathione stores further modulate the outcome of DILI. For example, diabetes increases the risk of acute liver failure,10 which may be related to diminished mitochondrial

function.8, 10, 11 In addition, approximately 1 in 8,000 adults harbor Mdm2 antagonist inherited pathogenic mitochondrial DNA mutations.12 Most drugs withdrawn from the market are mitochondrial toxicants, as are more than half of marketed drugs with black box warnings for hepatotoxicity or cardiotoxicity.13 Mitochondria are the key cellular energy source, supplying more than 90% of cellular ATP.13 Therefore, drug-induced mitochondrial impairment directly affects hepatocyte viability.8 Mitochondrial energy is largely generated by fatty acid oxidation; mitochondrial respiration also generates reactive oxygen species.13 Drugs or metabolites that inhibit the mitochondrial electron transport chain increase reactive Deforolimus cell line oxygen species and can trigger the mitochondrial permeability transition (depleting the mitochondrial membrane potential difference), resulting in cell death.8, 13 Nucleoside analogues for treatment of human immunodeficiency virus inhibit mitochondrial DNA synthesis in a concentration-dependent fashion, resulting in decreased mitochondrial

respiration and ATP and increased lactate.13 Drugs that are Cytidine deaminase lipophilic and cationic (such as tacrine) accumulate in mitochondria and increase the risk of mitochondrial toxicity.13 Cell death occurs when a critical number of a hepatocyte’s mitochondria are disabled.8 Upon withdrawal of mitochondrial toxicants, mitochondria can successfully regenerate over one to several weeks.14, 15 The likelihood of DILI is significantly increased in patients exhibiting polymorphisms of mitochondrial DNA polymerase gamma,16, 17 superoxide dismutase 2 (which scavenges mitochondrial superoxide),18 or specific human leukocyte antigen (HLA) markers associated with immunoallergic injury.19-23 Immunoallergic injury or hypersensitivity is associated with fever, rash, eosinophilia, and antidrug antibodies and occurs rapidly on rechallenge (sometimes within hours).