Mitigation of Methimazole-Induced Hepatic Injury by Taurine in Mice

Abstract

Methimazole is the most widely prescribed antithyroid medication in humans. However, hepatotoxicity is a deleterious adverse effect associated with methimazole administration. No specific protective agent has been developed against this complication yet. This study was designed to investigate the role of taurine as a hepatoprotective agent against methimazole-induced liver injury in mice. Different reactive metabolites were proposed to be responsible for methimazole hepatotoxicity. Hence, methimazole-induced liver injury was investigated in intact and/or enzyme-induced animals in the current investigation. Animals were treated with methimazole (200 mg/kg, by gavage), and hepatic injury induced by this drug was investigated in intact and/or enzyme-induced groups. Markers such as lipid peroxidation, hepatic glutathione content, alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in plasma, and histopathological changes in the liver of animals were monitored after drug administration. Methimazole caused liver injury as revealed by increased plasma ALT. Furthermore, a significant amount of lipid peroxidation was detected in the drug-treated animals, and hepatic glutathione reservoirs were depleted. Methimazole-induced hepatotoxicity was more severe in enzyme-induced mice. The above-mentioned alterations in hepatotoxicity markers were endorsed by significant histopathological changes in the liver. Taurine administration (1 g/kg, i.p.) effectively alleviated methimazole-induced liver injury in both intact and/or enzyme-induced animals.

Keywords: Antithyroid; Drug-induced liver injury (DILI); Endocrinology; Hepatoprotective.

Fig. 1

Methimazole-induced changes in plasmatic ALT levels over time. Data are expressed as Mean±SEM for six mice. Methimazole (200 mg/kg) was administered by gavage and plasma ALT level was assessed at different time points. * Indicates significantly higher than the control group (P<0.05)

Fig. 2

Methimazole-induced lipid peroxidation in mice livers. Data are expressed as Mean±SEM for six animals in each group. Mice were treated with methimazole (200 mg/kg, orally) and the level of lipid peroxidation was assessed after 5 hours of drug administration. MMI: methimazole, Enz-Ind: enzyme-induced animals. * Significantly higher than the control group (P<0.05). ^a Significantly higher than the MMI-treated group (P<0.05). ^b Significantly lower than the MMI-treated group (P<0.05). ^c Significantly lower than the enzyme-induced group which was treated with MMI (P<0.05)

Fig. 3

Effect of methimazole on hepatic glutathione reservoirs in mice. Data are given as Mean±SEM for six mice. MMI: methimazole, Enz-Ind: enzyme-induced animals. * Significantly higher than the control group (P<0.05). ^a Significantly higher than the MMI-treated group (P<0.05). ^b Significantly lower than the MMI-treated group (P<0.05). ^c Significantly lower than the enzyme-induced group which was treated with MMI (P<0.05)

Fig. 4

Histopathological changes in mice livers after methimazole administration in normal and/or enzyme-induced animals. Haematoxylin and eosin (H&E) staining. A: control (vehicle-treated), B: +methimazole (200 mg/kg), C: enzyme-induced animals + methimazole (200 mg/kg), D: methimazole + taurine (1 g/kg), E: methimazole + NAC (300 mg/kg), F: enzyme-induced + methimazole (200 mg/kg) + taurine (1 g/kg), G: enzyme-induced + methimazole (200 mg/kg) + NAC (300 mg/kg). Methimazole administration caused sinusoidal congestion and slight inflammatory cell infiltration in mice livers (B). When enzyme-induced animals were treated with methimazole, liver necrosis, inflammation, and hemorrhage occurred (C). Administration of taurine (D & F) and/or NAC (E & G), effectively alleviated methimazole-induced histopathological changes in the liver in both intact and/or enzyme-induced animals.

Fig. 5

The proposed hepatoprotective mechanisms of taurine and/or N-acetylcysteine (NAC) against methimazole-induced liver injury. CYP450: cytochrome P450, FMO: flavin-dependent monoxygenases