Article

IL-4 mediates dicloxacillin-induced liver injury in mice

Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Toxicology Letters (Impact Factor: 3.36). 02/2011; 200(3):139-45. DOI: 10.1016/j.toxlet.2010.11.006
Source: PubMed

ABSTRACT Drug-induced liver injury (DILI) is a major problem in drug development and clinical drug therapy. In most cases, the mechanisms are still unknown. It is difficult to predict DILI in humans due to the lack of experimental animal models. Dicloxacillin, penicillinase-sensitive penicillin, rarely causes cholestatic or mixed liver injury, and there is some evidence for immunoallergic idiosyncratic reaction in human. In this study, we investigated the mechanisms of dicloxacillin-induced liver injury. Plasma ALT and total-bilirubin (T-Bil) levels were significantly increased in dicloxacillin-administered (600 mg/kg, i.p.) mice. Dicloxacillin administration induced Th2 (helper T cells)-mediated factors and increased the plasma interleukin (IL)-4 level. Neutralization of IL-4 suppressed the hepatotoxicity of dicloxacillin, and recombinant mouse IL-4 administration (0.5 or 2.0 μg/mouse, i.p.) exacerbated it. Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) is a cognate receptor for prostaglandin (PG) D(2), and is suggested to be involved in Th2-dependent allergic inflammation. We investigated the effect of 13,14-Dihydro-15-keto-PGD(2) (DK-PGD(2); 10 μg/mouse, i.p.) administration on dicloxacillin-induced liver injury. DK-PGD(2)/dicloxacillin coadministration resulted in a significant increase of alanine aminotransferases and a remarkable increase of macrophage inflammatory protein 2 expression. In conclusion, to the best of our knowledge, this is the first report to demonstrate that dicloxacillin-induced liver injury is mediated by a Th2-type immune reaction and exacerbated by DK-PGD(2).

0 Bookmarks
 · 
95 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical pharmacotherapy. However, prediction of DILI is difficult because the underlying mechanisms are not fully understood. To establish a novel cell-based screening system to suggest drugs with hepatotoxic potential in preclinical drug development, comprehensive gene expression analyses during in vivo DILI are necessary. Using in vivo mouse DILI models and 4 sets of hepatotoxic positive and non-hepatotoxic drugs, we found that the hepatic mRNA levels of S100A8; S100A9; “NATCH, LRR, and pyrin domain-containing protein 3” (NALP3); interleukin (IL)-1β; and the receptor for advanced glycation endproducts (RAGE) were commonly increased in hepatotoxic drug-administered mice compared to non-hepatotoxic drug-administered mice. To clarify whether these 5 in vivo biomarkers can be applied to a cell-based screening system, we adapted human liver microsomes (HLM) in the presence of NADPH to assess the metabolic activation reaction, and we also adapted human monocytic leukemia cells HL-60, K562, KG-1 and THP-1 to assess the effects on mRNA expression of immune- and inflammatory-related factors. We investigated 30 clinical drugs with different safety profiles with regard to DILI and found that the total sum score of gene expression levels of S100A8, S100A9, RAGE, NALP3 and IL-1β mRNA in HL-60 or K562 cells incubated with HLM, could identify drugs at high risk for hepatotoxicity. We proposed the use of the total sum score of gene expression level for assessing metabolic activation by drug-metabolizing enzymes and immune- and inflammatory-related factors for the risk assessment of DILI in preclinical drug development.
    Toxicology Letters 07/2014; DOI:10.1016/j.toxlet.2014.04.005 · 3.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Liver eosinophilia has been associated with incidences of drug-induced liver injury (DILI) for more than 50 years, although its role in this disease has remained largely unknown. In this regard, we recently showed for the first time that eosinophils played a pathogenic role in a mouse model of halothane-induced liver injury (HILI). However, the signaling events that drove hepatic expression of eosinophil associated chemokines, eotaxins, eosinophil infiltration, and subsequent HILI were unclear. We now provide evidence implicating hepatic epithelial derived cytokine thymic stromal lymphopoietin (TSLP) and type 2 immunity, in particular interleukin-4 (IL-4) production, in mediating hepatic eosinophilia and injury during HILI. TSLP was constitutively expressed by mouse hepatocytes and increased during HILI. Moreover, the severity of HILI was reduced in mice deficient in either the TSLP receptor (TSLPR) or IL-4 and was accompanied by decreases in serum levels of eotaxins and hepatic eosinophilia. Similarly, concanavalin A-induced liver injury, where type 2 cytokines and eosinophils play a significant role in its pathogenesis, was also reduced in TSLPR-deficient mice. Studies in vitro revealed that mouse and human hepatocytes produce TSLP and eotaxins in response to treatment with combinations of IL-4 and pro-inflammatory cytokines IL-1β and tumor necrosis factor-α. Conclusion: This report provides the first evidence implicating roles for hepatic TSLP signaling, type 2 immunity, and eosinophilia in mediating liver injury caused by a drug. (Hepatology 2014;)
    Hepatology 04/2014; 60(5). DOI:10.1002/hep.27169 · 11.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Drug-induced hepatotoxicity is a significant cause of acute liver failure and is usually the primary reason that therapeutic drugs are removed from the commercial market. Multiple mechanisms can culminate in drug hepatotoxicity. Metabolism, genetics and immunology separately and in concert play distinct and overlapping roles in this process. This review will cover papers we feel have addressed these mechanisms of drug-induced hepatotoxicity in adults following the consumption of commonly used medications. The aim is to generate discussion around "trigger point" papers where the investigators generated new science or provided additional contribution to existing science. Hopefully these discussions will assist in uncovering key areas that need further attention.
    International Journal of Molecular Sciences 04/2014; 15(4):6990-7003. DOI:10.3390/ijms15046990 · 2.34 Impact Factor