Pharmaceutical Sciences Faculty Publications

Increased Oxidative-Modifications of Cytosolic Proteins in 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy)-Exposed Rat Liver

Document Type

Article

Publication Date

1-1-2011

Journal Title

Proteomics

ISSN

1615-9861

Volume

11

Issue

2

First Page

202

Last Page

211

DOI

10.1002/pmic.201000203

PubMed ID

21204248

PubMed Central® ID

PMC3335435

Abstract

It is well established that 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) causes acute liver damage in animals and humans. The aim of this study was to identify and characterize oxidative modification and inactivation of cytosolic proteins in MDMA-exposed rats. Markedly increased levels of oxidized and nitrated cytosolic proteins were detected 12 h after the second administration of two consecutive MDMA doses (10 mg/kg each). Comparative 2-DE analysis showed markedly increased levels of biotin-N-methylimide-labeled oxidized cytosolic proteins in MDMA-exposed rats compared to vehicle-treated rats. Proteins in the 22 gel spots of strong intensities were identified using MS/MS. The oxidatively modified proteins identified include anti-oxidant defensive enzymes, a calcium-binding protein, and proteins involved in metabolism of lipids, nitrogen, and carbohydrates (glycolysis). Cytosolic superoxide dismutase was oxidized and its activity significantly inhibited following MDMA exposure. Consistent with the oxidative inactivation of peroxiredoxin, MDMA activated c-Jun N-terminal protein kinase and p38 kinase. Since these protein kinases phosphorylate anti-apoptotic Bcl-2 protein, their activation may promote apoptosis in MDMA-exposed tissues. Our results show for the first time that MDMA induces oxidative-modification of many cytosolic proteins accompanied with increased oxidative stress and apoptosis, contributing to hepatic damage.

Keywords

Cytosol, enzyme activation, hallucinogens, liver, nitrogen, oxidation-reduction, proteins, proto-oncogene Proteins, sprague-dawley

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