Effects of Enzyme Induction and/or Glutathione Depletion on Methimazole-Induced Hepatotoxicity in Mice and the Protective Role of N-Acetylcysteine

  • Adv Pharm Bull. 2014;4(1):21-8. doi: 10.5681/apb.2014.004.
Reza Heidari  1 ,  Hossein Babaei  1 ,  Leila Roshangar  2 ,  Mohammad Ali Eghbal  1
Affiliations
  • 1. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. ; Pharmacology and Toxicology Department, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
  • 2. Anatomical Sciences Department, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
PMID: 24409405 DOI: 10.5681/apb.2014.004
Abstract

Purpose: Methimazole is the most convenient drug used in the management of hyperthyroid patients. However, associated with its clinical use is hepatotoxicity as a life threatening adverse effect. The exact mechanism of methimazole-induced hepatotoxicity is still far from clear and no protective agent has been developed for this toxicity.

Methods: This study attempts to evaluate the hepatotoxicity induced by methimazole at different experimental conditions in a mice model. Methimazole-induced hepatotoxicity was investigated in different situations such as enzyme induced and/or glutathione depleted Animals.

Results: Methimazole (100 mg/kg, i.p) administration caused hepatotoxicity as revealed by increase in serum alanine aminotransferase (ALT) activity as well as pathological changes of the liver. Furthermore, a significant reduction in hepatic glutathione content and an elevation in lipid peroxidation were observed in methimazole-treated mice. Combined administration of L-buthionine sulfoximine (BSO), as a glutathione depletory agent, caused a dramatic change in methimazole-induced hepatotoxicity characterized by hepatic necrosis and a severe elevation of serum ALT activity. Enzyme induction using phenobarbital and/or β-naphtoflavone beforehand, deteriorated methimazole-induced hepatotoxicity in mice. N-acetyl cysteine (300 mg/kg, i.p) administration effectively alleviated hepatotoxic effects of methimazole in both glutathione-depleted and/or enzyme induced Animals.

Conclusion: The severe hepatotoxic effects of methimazole in glutathione-depleted Animals, reveals the crucial role of glutathione as a cellular defense mechanism against methimazole-induced hepatotoxicity. Furthermore, the more hepatotoxic properties of methimazole in enzyme-induced mice, indicates the role of reactive intermediates in the hepatotoxicity induced by this drug. The protective effects of N-acetylcysteine could be attributed to its radical/reactive metabolite scavenging, and/or antioxidant properties as well as glutathione replenishment activities.

Keywords
Enzyme induction; Glutathione; Hepatotoxicity; Methimazole; Mice; N-acetyl cysteine.
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