Inflammatory stress and idiosyncratic hepatotoxicity: hints from animal models

Abstract

Adverse drug reactions (ADRs) present a serious human health problem. They are major contributors to hospitalization and mortality throughout the world (Lazarou et al., 1998; Pirmohamed et al., 2004). A small fraction (less than 5%) of ADRs can be classified as "idiosyncratic." Idiosyncratic ADRs (IADRs) are caused by drugs with diverse pharmacological effects and occur at various times during drug therapy. Although IADRs affect a number of organs, liver toxicity occurs frequently and is the primary focus of this review. Because of the inconsistency of clinical data and the lack of experimental animal models, how IADRs arise is largely undefined. Generation of toxic drug metabolites and induction of specific immunity are frequently cited as causes of IADRs, but definitive evidence supporting either mechanism is lacking for most drugs. Among the more recent hypotheses for causation of IADRs is that inflammatory stress induced by exogenous or endogenous inflammagens is a susceptibility factor. In this review, we give a brief overview of idiosyncratic hepatotoxicity and the inflammatory response induced by bacterial lipopolysaccharide. We discuss the inflammatory stress hypothesis and use as examples two drugs that have caused IADRs in human patients: ranitidine and diclofenac. The review focuses on experimental animal models that support the inflammatory stress hypothesis and on the mechanisms of hepatotoxic response in these models. The need for design of epidemiological studies and the potential for implementation of inflammation interaction studies in preclinical toxicity screening are also discussed briefly.

Fig. 1.

Proposed mechanism of LPS/RAN-induced liver injury. RAN augments TNFα production after LPS treatment in a post-transcriptional manner by enhancing p38 activation. The increase in TNFα protein occurs through the p38-dependent activation of TACE. The prolongation of LPS-induced TNF-α production by RAN seems to be crucial for liver injury. TNFα leads to coagulation system activation and PAI-1 production, both of which cause hepatic fibrin deposition. PAI-1 might also contribute to the activation of hepatic PMNs accumulated after LPS exposure. The hypoxia resulting from hepatic fibrin deposition and perhaps other factors could act synergistically with toxic proteases released from activated PMNs to kill hepatocytes. PMN proteases are also involved in enhancing PAI-1 production and fibrin deposition. HPC, hepatic parenchymal cell; STC, hepatic stellate cell; Trans-factor(s), transcription factor(s).

Fig. 2.

Working hypothesis for DCLF-induced hepatocellular injury. DCLF could cause hepatocellular injury through different modes depending on the dose. A nontoxic dose of DCLF interacts with an independently generated inflammatory stress (e.g., from LPS translocation) to produce hepatocellular injury in rats through a PMN-dependent mechanism. Large, toxic doses of DCLF cause hepatotoxicity through a mechanism that depends on gut-derived bacteria/LPS and probably do so by inducing oxidative stress and apoptotic signaling or altering lipid metabolism. Mito, mitochondrial.

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.