Mechanism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-mediated mitochondrial dysfunction in rat liver
Open accessAbstract
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.
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Similar numbers of oxidatively-modified mitochondrial proteins were identified by mass-spectral analysis in mice with I/R injury and rats exposed to MDMA.
“Similar numbers of oxidatively-modified mitochondrial proteins were also identified by mass-spectral analysis in mice with I/R injury [38] and rats exposed to 3,4-methylenedioxymethamphetamine (MDMA) [39].”
Similar modifications and inactivation of active site Cys residues in thiolase and possibly other enzymes in the β-oxidation pathway of fatty acids are likely to lead to fat accumulation observed in alcohol-exposed rodents, MDMA-exposed rats and mouse liver following I/R injury.
“Similar modifications and inactivation of active site Cys residues in thiolase and possibly other enzymes in the β-oxidation pathway of fatty acids are likely to lead to fat accumulation observed in alcohol-exposed rodents [34], in MDMA-exposed rats [39] as well as in mouse liver following I/R injury [38].”
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Self-citation
- Authors
- Moon, K., Upreti, V. V., Yu, L., Lee, I. J., Ye, X., Eddington, N. D., Veenstra, T. D., & Song, B.
- Affiliations
- National Institute on Alcohol Abuse and Alcoholism (US)
- University of Maryland, Baltimore (US)
- National Center for Toxicological Research (US)
- National Cancer Institute (US)
- Corresponding author
- Song, Byoung‐Joon
- Venue
- PROTEOMICS
- Publisher
- Wiley
- Published
- 2008-09
- Volume
- 8
- Issue
- 18
- Pages
- 3906-3918
- ISSN
- 1615-9853 (ISSN-L)
- 1615-9861
- PMC
- PMC2590641
- OpenAlex
- W2033243193
- Cited by
- 62
- References
- 51
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 1 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 6 · 2014: 5 · 2013: 10 · 2012: 5
- FWCI
- 5.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- PROTEOMICS (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DigitalCommons-Cedarville (Cedarville University) (submittedVersion)
- Funders
- Intramural Research Program of National Institute on Alcohol Abuse and Alcoholism
- National Cancer Institute, National Institutes of Health (NO1-CO-12400)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
- Keywords
- MDMA, ecstasy, hepatotoxicity, mitochondrial dysfunction, protein oxidation, mitochondrial aldehyde dehydrogenase, 3-ketoacyl-CoA thiolase, ATP synthase, liver injury, hydrogen peroxide, nitric oxide synthase
- MeSH terms
- Transaminases, Animals, Biotin, Hallucinogens, Hydrogen Peroxide, Liver, Male, Maleimides, Mitochondria, Liver, Oxidation-Reduction, Rats, Sprague-Dawley, Oxidative Stress, N-Methyl-3,4-methylenedioxyamphetamine, Nitric Oxide Synthase, Rats, Tandem Mass Spectrometry
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