Pharmaceutical Sciences Faculty Publications
Mechanism of 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy)-Mediated Mitochondrial Dysfunction in Rat Liver
Document Type
Article
Publication Date
9-1-2008
Journal Title
Proteomics
ISSN
1615-9861
Volume
8
Issue
18
First Page
3906
Last Page
3918
DOI
10.1002/pmic.200800215
PubMed ID
18780394
PubMed Central® ID
PMC2590641
Abstract
Despite numerous reports citing the acute hepatotoxicity caused by 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy), the underlying mechanism of organ damage is poorly understood. We hypothesized that key mitochondrial proteins are oxidatively modified and inactivated in MDMA-exposed tissues. The aim of this study was to identify and investigate the mechanism of inactivation of oxidatively modified mitochondrial proteins, prior to the extensive mitochondrial dysfunction and liver damage following MDMA exposure. MDMA-treated rats showed abnormal liver histology with significant elevation in plasma transaminases, nitric oxide synthase, and the level of hydrogen peroxide. Oxidatively modified mitochondrial proteins in control and MDMA-exposed rats were labeled with biotin-N-maleimide (biotin-NM) as a sensitive probe for oxidized proteins, purified with streptavidin-agarose, and resolved using 2-DE. Comparative 2-DE analysis of biotin-NM-labeled proteins revealed markedly increased levels of oxidatively modified proteins following MDMA exposure. Mass spectrometric analysis identified oxidatively modified mitochondrial proteins involved in energy supply, fat metabolism, antioxidant defense, and chaperone activities. Among these, the activities of mitochondrial aldehyde dehydrogenase, 3-ketoacyl-CoA thiolases, and ATP synthase were significantly inhibited following MDMA exposure. Our data show for the first time that MDMA causes the oxidative inactivation of key mitochondrial enzymes which most likely contributes to mitochondrial dysfunction and subsequent liver damage in MDMA-exposed animals.
Keywords
Biotin, hallucinogens, hydrogen peroxide, liver, maleimides, mitochondria, nitric oxide synthase, rats, sprague-dawley, tandem mass spectrometry, transaminases
Recommended Citation
Moon, Kwan-Hoon; Upreti, Vijay V.; Yu, Li-Rong; Lee, Insong J.; Ye, Xiaoying; Eddington, Natalie D.; Veenstra, Timothy D.; and Song, Byoung-Joon, "Mechanism of 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy)-Mediated Mitochondrial Dysfunction in Rat Liver" (2008). Pharmaceutical Sciences Faculty Publications. 322.
https://digitalcommons.cedarville.edu/pharmaceutical_sciences_publications/322
