Signal Transduction Pathways Involved in Drug-Induced Liver Injury

摘要: Hepatocyte death following drug intake is the critical event in clinical manifestation of drug-induced liver injury (DILI). Traditionally, hepatocyte caused by drugs had been attributed to overwhelming oxidative stress and mitochondria dysfunction reactive metabolites formed during metabolism. However, recent studies have also shown that signal transduction pathways activated/inhibited play a key role DILI. In acetaminophen (APAP)-induced injury, requires sustained activation c-Jun kinase (JNK), important mediating apoptotic necrotic death. Inhibition JNK using chemical inhibitors or knocking down can prevent even presence extensive glutathione (GSH) depletion, covalent binding, stress. Once activated, translocates mitochondria, induce permeability transition trigger Mitochondria are central targets where prodeath kinases such as JNK, prosurvival proteins bcl-xl, damage converge determine survival. The importance DILI observed Mn-SOD heterozygous (+/−) model, mice with less mitochondrial sensitized certain drugs. An body research accumulating suggesting Drugs cause redox changes inhibit NF-κB. inhibition NF-κB subtoxic doses APAP sensitizes cytotoxic actions tumor necrosis factor (TNF). Many will if simultaneously treated LPS, which promotes inflammation cytokine release. may be sensitizing hepatocytes effects cytokines TNF, vice versa. Overall many signaling regulating DILI, represent potential therapeutic reduce