Cytokines as potential biomarkers of liver toxicity.

Several important drug classes show pre-clinical hepatotoxicity or, in some cases hepatotoxicity in man in Phase III/IV not predicted by pre-clinical studies. This hepatotoxicity is associated with death of the parenchyma by both necrosis and apoptosis. Recent data have implicated molecular mediators of the immune response such as tumor necrosis factor alpha (TNFalpha), interleukin 1beta(1L-1beta) and interleukin 6 (IL6) in acute and chronic liver damage. These cytokines networks have been implicated in mediating the hepatic response to xenobiotics as diverse as PPAR ligands, acetaminophen and phenobarbitone. Thus, pro-inflammatory cytokines such as TNFalpha, IL1 beta and IL6 are released into the bloodstream both from the liver and from distal sites during hepatic toxic injury. Probably due to differences in the responses of rodent and human hepatocytes to cytokines, some clinical hepatotoxicities are not predicted by rodent models. However, the cytokine changes implicated in this human hepatic cell death could be manifest in rodent models and thus could be detected at the molecular level. Here we review the role of cytokines in different types of drug-induced liver injury and discuss whether these cytokine fingerprints are potential biomarkers of so-called idiosyncratic human liver toxicity.