Paper Information

Journal:   ADVANCED PHARMACEUTICAL BULLETIN   2014 , Volume 4 , Number 1; Page(s) 21 To 28.
 
Paper: 

EFFECTS OF ENZYME INDUCTION AND/OR GLUTATHIONE DEPLETION ON METHIMAZOLE-INDUCED HEPATOTOXICITY IN MICE AND THE PROTECTIVE ROLE OF N-ACETYLCYSTEINE

 
 
Author(s):  HEIDARI REZA, BABAEI HOSSEIN, ROSHANGAR LEILA, EGHBAL MOHAMMAD ALI*
 
* TABRIZ UNIVERSITY OF MEDICAL SCIENCES, PHARMACOLOGY AND TOXICOLOGY DEPARTMENT, FACULTY OF PHARMACY, TABRIZ, IRAN
 
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
b-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.

 
Keyword(s): ENZYME INDUCTION, GLUTATHIONE, HEPATOTOXICITY, METHIMAZOLE, MICE, N-ACETYLCYSTEINE
 
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