Fig. 3.

Integration of the “inflammation hypothesis” with other hypotheses for etiology of idiosyncratic hepatotoxicity. Inflammation can influence a drug's propensity to cause idiosyncratic toxicity by several modes. For example, inflammatory cytokines can increase the concentration of a drug by inhibiting P450 expression. Activated leukocytes have also been implicated in metabolism of drugs to reactive species. Modification of proteins by these metabolites could result in hapten formation and, upon rechallenge, precipitation of an adaptive immune response, which during a concurrent inflammatory stress (i.e., as a danger signal) might cause hepatotoxicity. Finally, the ability of a drug to alter hepatocellular homeostasis might render the liver sensitive to injury from normally noninjurious activation of inflammatory mediators.