Adv Pharm Bull. 2014;4(1):21-28.
doi: 10.5681/apb.2014.004
PMID: 24409405
PMCID: PMC3885364
  Abstract View: 276
  PDF Download: 239

Original Research

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

Reza Heidari 1,2, Hossein Babaei 1,2, Leila Roshangar 3, Mohammad Ali Eghbal 1,2 *

1 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
2 Pharmacology and Toxicology Department, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
3 Anatomical Sciences Department, Faculty of Medicine, Tabriz University of Medical Sciences, 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 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.
First name
 
Last name
 
Email address
 
Comments
 
Security code


Submitted: 12 May 2013
Revised: 12 Jun 2013
First published online: 23 Dec 2013
EndNote EndNote

(Enw Format - Win & Mac)

BibTeX BibTeX

(Bib Format - Win & Mac)

Bookends Bookends

(Ris Format - Mac only)

EasyBib EasyBib

(Ris Format - Win & Mac)

Medlars Medlars

(Txt Format - Win & Mac)

Mendeley Web Mendeley Web
Mendeley Mendeley

(Ris Format - Win & Mac)

Papers Papers

(Ris Format - Win & Mac)

ProCite ProCite

(Ris Format - Win & Mac)

Reference Manager Reference Manager

(Ris Format - Win only)

Refworks Refworks

(Refworks Format - Win & Mac)

Zotero Zotero

(Ris Format - FireFox Plugin)