IL-4 mediates dicloxacillin-induced liver injury in mice

Higuchi, Satonori; Kobayashi, Masanori; Yoshikawa, Yukitaka; Tsuneyama, Koichi; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

doi:10.1016/j.toxlet.2010.11.006

Cited by 38 publications

(26 citation statements)

References 29 publications

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“…Since the development of our model we have confirmed roles for immune activation triggered by IL-4 in patients by demonstrating CYP2E1 IgG4 autoantibodies in patients with anesthetic DILI [35–37]. Another study that clearly investigated the immunological role of IL-4 in the initiation of immune mediated hepatitis showed that IL-4 initiated and augmented hepatotoxicity following dicloxacillin [38] utilizing blocking antibody and recombinant IL-4, respectively. Together these studies demonstrated that T cell activation in an IL-4 environment initiates drug-induced hepatic inflammation and hepatotoxicity in animal models and most likely immune-mediated hepatotoxicity in patients.…”

Section: Immune Basis Of Drug Hepatotoxicitymentioning

confidence: 67%

Drug-Induced Hepatotoxicity: Metabolic, Genetic and Immunological Basis

Njoku

2014

IJMS

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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.

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Section: Immune Basis Of Drug Hepatotoxicitymentioning

confidence: 67%

Drug-Induced Hepatotoxicity: Metabolic, Genetic and Immunological Basis

Njoku

2014

IJMS

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“…Metabolites of AMD produced by CYP3A4 were previously suggested to be involved in AMD‐induced hepatotoxicity in cell‐based in vitro assays (Endo et al ., ; Hosomi et al ., ; Waldhauser et al ., ; Zahno et al ., ); however, there are no reports demonstrating the involvement of the metabolites in liver injury in vivo experimental animals. The involvement of immunity‐ and inflammatory‐related factors in the development of DILI, which are difficult to assess with in vitro experiments, was demonstrated by mouse models of dicloxacillin‐(Higuchi et al ., ), diclofenac‐(Yano et al ., ), flutamide‐(Higuchi et al ., ), halothane‐(Kobayashi et al ., ) and methimazole‐(Kobayashi et al ., ) induced liver injury established by our group. In this study, we aimed to clarify the involvement of immunity‐ and inflammatory‐related factors and metabolic activation reactions in AMD‐induced liver injury in a mouse model.…”

Section: Discussionmentioning

confidence: 99%

Establishment of a mouse model for amiodarone‐induced liver injury and analyses of its hepatotoxic mechanism

Takai

Oda

Tsuneyama

et al. 2015

J of Applied Toxicology

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Drug-induced liver injury (DILI) is the most frequent cause of post-marketing warnings and withdrawals. Amiodarone (AMD), an antiarrhythmic, presents a risk of liver injury in humans, and its metabolites, formed by cytochrome P450 3A4, are likely more toxic to hepatocytes than AMD is. However, it remains to be clarified whether the metabolic activation of AMD is involved in liver injury in vivo. In this study, to elucidate the underlying mechanisms of AMD-induced liver injury, mice were administered AMD [1000 mg kg(-1), per os (p.o.)] after pretreatment with dexamethasone [DEX, 60 mg kg(-1), intraperitoneal (i.p.)], which induces P450 expression, once daily for 3 days. The plasma alanine aminotransferase (ALT) levels were significantly increased by AMD administration in the DEX-pretreated mice, and the liver concentrations of desethylamiodarone (DEA), a major metabolite of AMD, were correlated with the changes in the plasma ALT levels. Cytochrome c release into the hepatic cytosol and triglyceride levels in the plasma were increased in DEX plus AMD-administered mice. Furthermore, the ratio of reduced glutathione to oxidized glutathione disulfide in the liver significantly decreased in the DEX plus AMD-administered mice. The increase of ALT levels was suppressed by treatment with gadolinium chloride (GdCl3 ), which is an inhibitor of Kupffer cell function. From these results, it is suggested that AMD and/or DEA contribute to the pathogenesis of AMD-induced liver injury by producing mitochondrial and oxidative stress and Kupffer cell activation. This study proposes the mechanisms of AMD-induced liver injury using an in vivo mouse model.

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“…MTZ is metabolized by cytochrome P450 and flavin-containing monooxygenase (FMO), and metabolites, such as N-methylthiourea and glyoxal, are suggested to have an important role in MTZ-induced liver injury (Heidari et al, 2014). Recent studies have also indicated that Th2 cytokine-mediated immune responses were involved in flutamide-or dicloxacillin-induced liver injury in mouse models (Higuchi et al, 2011;Higuchi et al, 2012). Th cells organize the immune response via cytokine production, and naïve, CD4-positive Th cells commonly differentiate into Th1, Th2, Th17, and regulatory T-cell subsets.…”

Section: Introductionmentioning

confidence: 99%

Kupffer cell‐mediated exacerbation of methimazole‐induced acute liver injury in rats

Akai

Uematsu

Tsuneyama

et al. 2015

J of Applied Toxicology

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Methimazole (MTZ), an anti-thyroid drug, is known to cause liver injury in humans. It has been demonstrated that MTZ-induced liver injury in Balb/c mice is accompanied by T helper (Th) 2 cytokine-mediated immune responses; however, there is little evidence for immune responses associated with MTZ-induced liver injury in rats. To investigate species differences in MTZ-induced liver injury, we administered MTZ with a glutathione biosynthesis inhibitor, L-buthionine-S,R-sulfoximine (BSO), to F344 rats and subsequently observed an increase in plasma alanine aminotransferase (ALT) and high-mobility group box 1 (HMGB1), which are associated with hepatic lesions. The hepatic mRNA expression of innate immune-related genes significantly increased in BSO- and MTZ-treated rats, but the change in Th2-related genes was not much greater than the change observed in the previous mouse study. Moreover, an increase in Kupffer cells and an induction of the phosphorylation of extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK) proteins were accompanied by an increase in Toll-like receptor 4 (TLR4) expression, indicating that Kupffer cell activation occurs through HMGB1-TLR4 signaling. To elucidate the mechanism of liver injury in rats, gadolinium chloride, which inactivates the function of Kupffer cells, was administered before BSO and MTZ administration. The gadolinium chloride treatment significantly suppressed the increased ALT, which was accompanied by decreased hepatic mRNA expression related to innate immune responses and ERK/JNK phosphorylation. In conclusion, Kupffer cell-mediated immune responses are crucial factors for the exacerbation of MTZ-induced liver injury in rats, indicating apparent species differences in the immune-mediated exacerbation of liver injury between mice and rats.

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IL-4 mediates dicloxacillin-induced liver injury in mice

Cited by 38 publications

References 29 publications

Drug-Induced Hepatotoxicity: Metabolic, Genetic and Immunological Basis

Drug-Induced Hepatotoxicity: Metabolic, Genetic and Immunological Basis

Establishment of a mouse model for amiodarone‐induced liver injury and analyses of its hepatotoxic mechanism

Kupffer cell‐mediated exacerbation of methimazole‐induced acute liver injury in rats

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