Th2 cytokine‐mediated methimazole‐induced acute liver injury in mice

Abstract

Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical practice. The pathogenesis of DILI usually involves the participation of the parent drug or metabolites that either affect cellular function or elicit an immune response. However, the mechanisms leading to DILI are unknown in most cases. Methimazole (MTZ) is used as an antithyroid drug and is well known to have induced liver injuries such as cholestatic hepatitis in a small number of human cases. Immune-mediated reactions were also suggested to play a role in MTZ-induced acute liver injury, but the mechanism underlying this process has not been elucidated. To address this issue, we measured plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, hepatic glutathione levels, hepatic expression of CD4⁺ Th cell-related transcriptional factors, cytokines and chemokines, plasma interleukin (IL)-4 levels and histopathological changes in the liver following MTZ (450 mg kg⁻¹ , p.o.) administration in mice. The hepatic expression of mRNA for Th2 cell-related factors, such as GATA-binding protein, macrophage inflammatory protein-2 (MIP-2) and plasma IL-4 levels, as well as plasma AST and ALT levels, was significantly increased in mice treated with MTZ. These changes were markedly enhanced by pre-treatment with L-buthionine sulfoximine (3 mmol kg⁻¹, i.p.) and MTZ (15 mg kg⁻¹, p.o.). Neutralization of IL-4 using a monoclonal anti-mouse IL-4 antibody (100 µg/mouse, single i.p.) suppressed the hepatotoxic effect of MTZ. In conclusion, this report is the first to demonstrate that Th2 cytokine-mediated immune responses are involved in MTZ-induced acute liver injury in mice.

Carbamazepine-Induced Liver Injury Requires CYP3A-Mediated Metabolism and Glutathione Depletion in Rats

“…2A). Many researchers have applied GSH-depleted animal models using BSO to evaluate the hepatotoxic potential of several drugs (Nishiya et al, 2008;Shimizu et al, 2009Shimizu et al, , 2011Kobayashi et al, 2012a). Therefore, BSO (700 mg/kg) was intraperitoneally injected 2 hours prior to the oral CBZ administration; however, the plasma ALT levels were not increased ( Fig.…”

“…Some researchers have established animal models of drug-induced liver injury, such as trovafloxacilin and sulindac, using lipopolysaccharide to study immune-mediated mechanisms (Shaw et al, 2007, Zou et al, 2009). In addition, it has been reported that GSH-depleted animal models using L-buthionine sulfoximine (BSO), which is an inhibitor of GSH synthesis, are useful for inducing sensitization to liver injury by such drugs as methimazole, tienilic acid, amodiaquine, and ticlopidine via reactive metabolite formations (Nishiya et al, 2008;Shimizu et al, 2009Shimizu et al, , 2011Kobayashi et al, 2012a).…”

“…In this study, BSO was used to deplete GSH to develop CBZ-induced liver injury in rats because BSO is known to be a specific inhibitor of g-glutamylcysteine synthetase, a rate-limiting enzyme of GSH synthesis (Griffith and Meister 1979), and can decrease the hepatic GSH content in rats (Gao et al, 2010). Many researchers have applied the GSH-depleted animal model using BSO to evaluate hepatotoxic potential for several drugs that are known to generate electrophilic reactive metabolites, such as methimazole, tienilic acid, amodiaquine, and ticlopidine (Nishiya et al, 2008;Shimizu et al, 2009Shimizu et al, , 2011Kobayashi et al, 2012a). In this study, several rats administered CBZ at a dose of 600 mg/kg or 800 mg/kg in combination with BSO on the 5th day showed severe hepatotoxicity, whereas rats administered CBZ alone showed no hepatotoxicity (Fig.…”

T‐helper cell‐mediated factors in drug‐induced liver injury

“…Acetaminophen-induced liver injury can be associated with disturbance of balance of Th1/Th2 cytokines into a Th1-dominant response (Masubuchi et al, 2009). Th2-related immune factors have been activated in methimazole-and flutamide-treated mice Kobayashi et al, 2012). Neutralization with antibody can suppress the hepatotoxicity that further proves the involvement of Th2-related immune factors.…”

Acute Hepatitis after Methimazole. Case Report

“…The mechanism could be related to the fact that it is a hepatic-metabolised drug. The pathogenesis of the liver injury usually involves the participation of the parent drug or metabolites that may affect cellular function or trigger an immune response (22). Immunemediated reactions were also suggested to play a role methimazole-induced acute liver injury.…”