Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical drug therapy. However, the underlying mechanism of DILI is little known. It is difficult to predict DILI in humans due to the lack of experimental animal models. Diclofenac, a non-steroidal anti-inflammatory drug rarely causes severe liver injury in human, but there is some evidence for immunoallergic idiosyncratic reactions. In this study, the mechanism of diclofenac-induced liver injury in mice was investigated. First, we established the dosing condition for liver injury in normal mice. Plasma ALT and AST levels were significantly increased in diclofenac-administered (80 mg/kg, i.p.) mice in a dose- and time-dependent manner. Among several interleukins (ILs) and chemokines, mRNA expression of helper T (Th) 17 cell-mediated factors, such as retinoid orphan receptor (ROR)-γt, and signal transducers and activators of transcription factor (STAT) 3 in the liver, and the plasma IL-17 level were significantly increased. Neutralization of IL-17 tended to suppress the hepatotoxicity of diclofenac, suggesting that IL-17 was partly involved. Gadolinium chloride (GdCl₃) administration demonstrated that Kupffer cells are not likely to be involved in diclofenac hepatotoxicity. Hepatic expressions of IL-1β mRNA and plasma IL-1β were significantly increased soon after the diclofenac administration. Then, the results of an in vivo neutralization study of IL-1β suggested that IL-1β was involved early in the time of pathogenesis of the diclofenac-induced liver injury. In conclusion, we firstly developed a diclofenac-induced acute liver injury model in normal mice, and the involvement of IL-17 and IL-1β was clarified.
"Naproxen and diclofenac are examples of Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) that are broadly used by the general population for minor ailments like headaches and muscle pains. Both compounds pose the risk of hepatotoxicity at high doses or with prolonged exposure (Triebskorn et al., 2004; Ali et al., 2011; Yano et al., 2012), but little information exists about the consequences of such effects in wildlife. The beta-blocker atenolol and lipid regulating drug gemfibrozil are commonly used for the treatment of high blood pressure and the regulation of cholesterol, respectively. "
[Show abstract][Hide abstract] ABSTRACT: Pharmaceutical contaminants represent emerging threats to aquatic animals and ecosystem health, and research exploring toxicological outcomes associated with these compounds in non-target wildlife has been flagged for prioritization. Amphibians represent particularly vulnerable organisms and many populations around the world are currently at risk of extinction. However, to date, relatively few studies have explored the consequences of exposures to common non-steroidal pharmaceuticals during sensitive amphibian life-stages. To address existing knowledge gaps, tadpoles of the Australian striped-marsh frog (Limnodynastes peronii) were exposed to control water and a mixture of the common pharmaceutical contaminants diclofenac, naproxen, atenolol and gemfibrozil at 0.1, 1, 10, 100 and 1000 μg/L throughout the developmental period. Effects on detoxification pathways, energy storage, growth and development, and swimming performance were assessed following exposure. Developmental rates and liver-somatic index (LSI) were significantly reduced in the highest exposure concentration, and condition factor (K) was increased at concentrations as low as 10 μg/L. Morphological endpoints were associated with significantly altered levels of hepatic triglycerides, which in turn were correlated with increased peroxidase activity in animals exposed to the highest concentration (1000 μg/L). The mixture had no significant effect on swimming performance, but a trend of decreased swimming velocity (average and maximum) was observed with increasing concentration, and this was correlated with effects on LSI. Results demonstrate that mixtures of common non-steroidal pharmaceuticals can elicit a range of physiological, metabolic and morphological responses in larval amphibians, and more research is therefore warranted to explore possible relationships between endpoints at different levels of organization.
"It is known that some cytokines are involved in DILI. Interferon (IFN)γ, IL-1β, IL-4 and IL-17 are involved in acetaminophen-, diclofenac-, methimazole-and halothane-induced liver injury, respectively (Ishida et al., 2002; Kobayashi et al., 2009, 2012; Yano et al., 2012). These cytokines contribute to immune cell activation , infiltration and cell apoptosis. "
"In line with previous studies that demonstrate a direct hepatotoxic effect of DF (Yano et al., 2012), we showed a protein profile in PCLS medium of all species treated with DF that is similar to that after APAP incubation. The presence of the same key proteins in PCLS medium was demonstrated by Western blotting. "
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.