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Xenobiotica
the fate of foreign compounds in biological systems
Volume 44, 2014 - Issue 1
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Molecular Toxicology

A new approach on methamphetamine-induced hepatotoxicity: involvement of mitochondrial dysfunction

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Pages 70-76 | Received 15 Apr 2013, Accepted 20 May 2013, Published online: 20 Jun 2013
 

Abstract

1. Methamphetamine (METH) is a highly addictive stimulant that is among the most widely abused illicit drugs. Clinical evidence has shown that the liver is a target of METH toxicity. The exact cellular and molecular mechanisms involved in METH-induced hepatotoxicity have not yet been completely understood.

2. In this study, the cellular pathways involved in METH liver toxicity were investigated in freshly isolated rat hepatocytes. METH cytotoxicity was associated with reactive oxygen species (ROS) formation, lipid peroxidation and rapid glutathione (GSH) depletion which is a third marker of cellular oxidative stress. Our results showed that the hepatocyte mitochondrial membrane potential (ΔΨm) was rapidly decreased by METH, which was prevented by antioxidants and ROS scavenger, suggesting that mitochondrial membrane damage was a consequence of ROS formation. Incubation of hepatocytes with METH also caused release of cytochrome c from mitochondria into the cytosol before cell lysis ensued.

3. Our findings showed that cytotoxic action of METH is mediated by oxidative stress and subsequent changes in mitochondrial membrane conformation and cytochrome c release into the cytosol which causes mitochondrial collapse of ΔΨm.

Acknowledgements

The results presented in this article were partly extracted from the thesis of Dr. Mokhtar Rahmati (Pham.D. graduate of School of Pharmacy, Zanjan University of Medical Sciences) who performed his thesis under the supervision of Dr. Mohammad Reza Eskandari.

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