Mechanistic review of drug-induced steatohepatitis.
Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other mechanisms discussed include the disruption of phospholipid metabolism in lysosomes, prevention of lipid egress from hepatocytes, targeting mitochondrial DNA and topoisomerase, decreasing intestinal barrier function, activation of the adenosine pathway, increasing fatty acid synthesis, and sequestration of coenzyme A. It has been found that the majority of compounds that induce steatohepatitis have cationic amphiphilic structures; a lipophilic ring structure with a side chain containing a cationic secondary or tertiary amine. Within the last decade, the ability of many chemotherapeutics to cause steatohepatitis has become more evident coining the term chemotherapy-associated steatohepatitis (CASH). The mechanisms behind drug-induced steatohepatitis are discussed with a focus on cationic amphiphilic drugs and chemotherapeutic agents.
Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA. Electronic address: Justin.d.schumacher@rutgers.edu.
Justin D
JD
Schumacher
Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA.
Grace L
GL
Guo
D000638:Amiodarone / Q000009:adverse effects; D000818:Animals; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000139:chemically induced / Q000473:pathology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008727:Methotrexate / Q000009:adverse effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000009:adverse effects; D000077150:Oxaliplatin; D010480:Perhexiline / Q000009:adverse effects; D013629:Tamoxifen / Q000009:adverse effects; D013752:Tetracycline / Q000009:adverse effects; D014635:Valproic Acid / Q000009:adverse effects
D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D013629:Tamoxifen; D014635:Valproic Acid; D000077146:Irinotecan; D013752:Tetracycline; D010480:Perhexiline; D000638:Amiodarone; D002166:Camptothecin; D008727:Methotrexate
Carnitine palmitoyltransferase-I; Cationic amphiphilic drugs; Chemotherapy-associated steatohepatitis; Drug-induced steatohepatitis; Mitochondrial toxicity