Modest Inflammation Enhances Diclofenac Hepatotoxicity in Rats: Role of Neutrophils and Bacterial Translocation

Abstract

Idiosyncratic adverse drug reactions (IADRs) represent an important human health problem, yet animal models for preclinical prediction of these reactions are lacking. Recent evidence in animals suggests that some IADRs arise from drug interaction with an inflammatory episode that renders the liver sensitive to injury. Diclofenac (DCLF) is one of those drugs for which the clinical use is limited by idiosyncratic liver injury. We tested the hypothesis that modest inflammation triggered in rats by a small dose of lipopolysaccharide (LPS) renders a nonhepatotoxic dose of DCLF injurious to liver. Cotreatment of rats with nonhepatotoxic doses of LPS and DCLF resulted in elevated serum alanine aminotransferase activity and liver histopathologic changes 6 h after DCLF administration. Neither LPS nor DCLF alone had such an effect. Gene array analysis of livers revealed a unique gene expression pattern in the LPS/DCLFcotreated group compared with groups given either agent alone. Antiserum-induced neutrophil (PMN) depletion in LPS/ DCLF-cotreated rats protected against liver injury, demonstrating a role for PMNs in the pathogenesis of this LPS/DCLF interaction. Gut sterilization of LPS/DCLF-treated rats did not protect against liver injury. In contrast, gut sterilization did attenuate liver injury caused by a large, hepatotoxic dose of DCLF, suggesting that hepatotoxicity induced by large doses of DCLF is caused in part by its ability to increase intestinal permeability to endotoxin or other bacterial products. These results demonstrate that inflammation-DCLF interaction precipitates hepatotoxicity in rats and raise the possibility of creating animal models that predict human IADRs.

Concurrent Inflammation Augments Antimalarial Drugs-Induced Liver Injury in Rats

“…On the other hand, the pathogenic role of other inflammatory cells such as neutrophils in the drug-inflammation interaction model is also mentioned in previous investigations. 23,50 Hence, neutrophils and other immune cells might also be responsible for the liver injury induced by AQ and CQ. Inhibition of these cells (e.g.…”

“…Several investigations indicated that the threshold for hepatotoxicity from many xenobiotics was lowered by co-exposure to LPS. 22,23,[40][41][42][43] The ability of LPS to stimulate an inflammatory response may account for its pathogenicity in the liver. LPS is a potent activator of liver tissue macrophages (Kupffer cells) through toll-like receptors (TLRs) (Figure 6).…”

“…20 The hepatotoxicity of many xenobiotics has been augmented in LPS-treated animals. [22][23][24] On the other side, malaria infection is associated with an inflammatory response in many tissues including liver. [25][26][27] Immune cells are aggregated in the liver of malaria-infected patients.…”

Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

“…This hypothesis is supported by the observation that neutrophil depletion protects against paracetamol toxicity [67] . Also, idiosyncratic reactions are more likely to occur in the presence of an inflammatory state [68] . Effectors are dendritic cells, which act by sensing pathogens and triggering adaptive immune responses.…”

Usefulness of <i>in vitro</i> combination assays of mitochondrial dysfunction and apoptosis for the estimation of potential risk of idiosyncratic drug induced liver injury

“…Based on this possible mechanism, there are some in vivo non-clinical animal models designed for the estimation of the idiosyncratic DILI. Lipopolysaccharide (LPS) co-treated rats have been reported to be one of the in vivo models to estimate the potential of idiosyncratic DILI for some drugs, including chlorpromazine (Buchweitz et al, 2002), diclofenac (Deng et al, 2006), ranitidine (Luyendyk et al, 2003), sulindac (Zou et al, 2009) and trovafloxacin . However, the utility of this model for the estimation of idiosyncratic DILI remains controversial because treatment with LPS intentionally destroys the immune system in normal rats.…”