Carbonyl Traps as Potential Protective Agents against Methimazole-Induced Liver Injury

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Carbonyl Traps as Potential Protective Agents against Methimazole-Induced Liver Injury

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Published Article
Journal of Biochemical and Molecular Toxicology
Wiley Blackwell (John Wiley & Sons)
DOI: 10.1002/jbt.21682
  • Molecular Biology
  • Health
  • Biochemistry
  • Toxicology
  • Molecular Medicine
  • Toxicology And Mutagenesis


Liver injury is a deleterious adverse ef-fect associated with methimazole administration, and reactive intermediates are suspected to be involved in this complication. Glyoxal is an expected reactive in-termediate produced during methimazole metabolism. Current investigation was undertaken to evaluate the role of carnosine, metformin, and N-acetyl cysteine as putative glyoxal (carbonyl) traps, against methimazole-induced hepatotoxicity. Methimazole (100 mg/kg, intraperitoneally) was administered to intact and/or glutathione (GSH)–depleted mice and the role of gly-oxal trapping agents was investigated. Methimazole caused liver injury as revealed by an increase in serum alanine aminotransferase and aspartate amino-transferase. Moreover, lipid peroxidation and protein carbonylation occurred significantly in methimazole– treated animals' liver. Hepatic GSH reservoirs were decreased, and inflammatory cells infiltration was ob-served in liver histopathology. Methimazole–induced hepatotoxicity was severe in GSH-depleted mice and accompanied with interstitial hemorrhage and necro-sis of the liver. Glyoxal trapping agents effectively di-minished methimazole-induced liver injury both in intact and/or GSH–depleted animals. INTRODUCTION Methimazole is the most prescribed drug for managing hyperthyroidism in humans [1]. However, hepatotoxicity is a deleterious side effect associated with methimazole administration [2, 3]. Although the precise mechanism(s) of liver injury induced by methimazole is not clear yet, but some investigations mentioned the role of reactive metabolite formation in its pathogenesis [4–6]. Methimazole is metabolized through cytochrome P450 and flavin–containing monoxygenases systems [7–10]. Different intermedi-ary metabolites are formed through the methimazole metabolism process, which are supposed to be toxic (Figure 1). Glyoxal and N–methylthiourea (Figure 1) are two suspected toxic metabolites for methimazole that are assumed to be involved in the cellular injury and liver damage induced by this drug [5, 6]. Despite many case reports indicating methimazole-induced hepatotoxicity [2, 11–13], no specific protective agent has been developed to treat antithyroid drugs-induced liver damage in hu-mans. Indeed, no clinical intervention except of drug cessation has been made for methimazole-induced liver injury in most case reports [3, 14–16]. Hence, finding new therapeutic strategies against antithyroids hepatotoxicity seems to have a great clinical benefit. As mentioned, glyoxal is an intermediary metabo-lite produced during methimazole metabolism [5] (Figure 1). Glyoxal is a well-known cytotoxic agent [17], which induces its toxic effects in different ways including oxidative stress induction [17, 18] and interaction with intracellular targets such as critical proteins, cellular mitochondria, or membrane lipids [17, 19]. Hence, we might be able to propose that

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