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

Abstract

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.

Cytochrome P450 1A1 and 1B1 promoter CpG island methylation regulates rat liver injury induced by isoniazid

“…Previous studies have indicated that the changes in TLR4, ERK, PPAR-γ signaling were regulated by CYPs, and were related to liver injury ( 17 – 21 ). Therefore, the relative mRNA expression levels of TLR4, ERK and PPAR-γ were evaluated by RT-qPCR following isoniazid exposure ( Fig.…”

“…Alterations in toll-like receptor (TLR)-4 mRNA expression and its signaling pathway were observed in liver injuries induced by acetaminophen, floxacillin, methimazole, lipopolysaccharide and alcohol ( 17 ). TLR4 has been reported to serve an important role in drug-induced liver injury, and TLR4 signal transduction cascades may be related to the cause of these diseases ( 18 ).…”

High‐Mobility Group Box‐1 and Liver Disease

“…(155) D-galactosamine increases HMGB1 release into plasma, correlating with a decrease in nuclear expression in rat liver (156) ; and, an HMGB1 neutralizing antibody suppressed plasma HMGB1 and inflammatory cytokines and improved liver injury and survival. (156) Methimazole increased plasma HMGB1 3-6 hours after exposure (157) ; this was ameliorated when Kupffer cell activation was blocked, suggesting that HMGB1 may be involved in mediating DILI by Kupffer cells. Rats treated with diclofenac had increased HMGB1 in plasma, (158) and sulfamethoxazole and flucloxacillin stimulated HMGB1 release from human hepatocytes along with markers of cell death and inflammation.…”

Establishment of a mouse model of troglitazone‐induced liver injury and analysis of its hepatotoxic mechanism

“…In vivo studies have shown that BSO pretreatment could enhance DILI caused by carbamazepine (Iida et al, ), methimazole (Akai et al, ) and phenytoin (Sasaki et al, ). However, in the studies presented here, the exacerbation of oxidative stress by the depletion of GSH showed an opposing role that reduced liver damage was caused by TGZ administration (Figure C).…”