Hepatotoxicity (DILI)

Hepatotoxicity refers to the injury or impairment of the liver caused by exposure to drugs, environmental chemicals, or other biological agents. It is not a biological target such as a receptor or enzyme; rather, it is a pathological state or side effect resulting from the toxic effects of various substances on hepatocytes and other liver cells (LiverTox, NIH). The liver is particularly susceptible to toxicity because it is the primary site for the metabolism of xenobiotics, often producing reactive intermediates via cytochrome P450 enzymes that can cause cellular damage (PubMed, PMID: 29241440). \n\nIn clinical development, hepatotoxicity—often termed Drug-Induced Liver Injury (DILI)—is a leading cause of drug candidate attrition and post-marketing regulatory actions. It can present as a wide spectrum of liver disease, including asymptomatic elevation of liver enzymes, cholestasis, steatosis, or fulminant hepatic failure. Because it is a clinical manifestation of toxicity and not a therapeutic target, drug discovery efforts focus on screening molecules to avoid hepatotoxicity rather than activating or inhibiting it (FDA, 2009; StatPearls, 2023).

Other names

Drug-induced liver injuryToxic hepatitisChemical-induced liver injuryLiver toxicity

Hepatotoxicity is a toxicological endpoint rather than a therapeutic target. It occurs through mechanisms such as oxidative stress, mitochondrial dysfunction, covalent binding of reactive metabolites to intracellular proteins, and immune-mediated hypersensitivity reactions (StatPearls, 2023; LiverTox, NIH).