Mechanistic review of drug-induced steatohepatitis

• Reviewed the mechanisms underlying drug-induced steatohepatitis for many compounds
• Mitochondrial dysfunction is critical in the development of drug-induced steatohepatitis.
• Majority of drugs that induce steatohepatitis are cationic amphiphilic drugs.
• Chemotherapeutics that induce CASH are cationic amphiphilic drugs.
• Majority of drugs that induce steatohepatitis are carnitine palmitoyltransferase-I inhibitors.

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.