GC-MS metabolomics reveals disturbed metabolic pathways in primary mouse hepatocytes exposed to subtoxic levels of 3,4-methylenedioxymethamphetamine (MDMA).
Ana Margarida Araújo, Maria de Lourdes Bastos, Eduarda Fernandes, Félix Carvalho, Márcia Carvalho, Paula Guedes de Pinho
Archives of Toxicology November 2018 DOI: 10.1007/s00204-018-2314-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro experimental study Peer reviewed |
|---|---|
| Population | Primary mouse hepatocytes (PMH) |
| Intervention | MDMA |
| Dose | two subtoxic concentrations of MDMA (LC01 and LC10) |
| Duration | 24 h |
| Topics | MDMA |
| Keywords | Hepatotoxicity Metabolomics Primary mouse hepatocytes Subtoxic concentrations |
| Key findings | Exposure of primary mouse hepatocytes to subtoxic MDMA concentrations for 24 hours produced a concentration-dependent metabolic signature, with LC10 increasing intracellular oleic and palmitic acids and decreasing glutamate, aspartate, 5-oxoproline, fumarate, malate, phosphoric acid, α-ketoglutarate and citrate, plus changes in extracellular volatile metabolites. The authors propose these alterations involve the TCA cycle, fatty acid and glutamate metabolism, and antioxidant defenses, and suggest some metabolites may serve as early biomarkers of MDMA hepatotoxicity. |
Abstract
3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a well-known hepatotoxic drug. Although its toxicity has been thoroughly studied at high concentrations, there is still insufficient knowledge on possible alterations of cell function at subtoxic concentrations, which are in fact more representative concentrations of intoxication scenarios. In this study, a gas chromatography-mass spectrometry (GC-MS) metabolomics approach was used to investigate the metabolic changes in primary mouse hepatocytes (PMH) exposed to two subtoxic concentrations of MDMA (LC01 and LC10) for 24 h. Metabolomic profiling of both intracellular metabolites and volatile metabolites in the extracellular medium of PMH was performed. Multivariate analysis showed that the metabolic pattern of cells exposed to MDMA discriminates from the controls in a concentration-dependent manner. Exposure to LC10 MDMA induces a significant increase in some intracellular metabolites, including oleic acid and palmitic acid, and a decrease in glutamate, aspartate, 5-oxoproline, fumarate, malate, phosphoric acid, α-ketoglutarate and citrate. Extracellular metabolites such as acetophenone, formaldehyde, pivalic acid, glyoxal and 2-butanone were found significantly increased after exposure to MDMA, compared to controls, whereas 4-methylheptane, 2,4-dimethyl-1-heptene, nonanal, among others, were found significantly decreased. The panel of discriminatory metabolites is mainly involved in tricarboxylic acid (TCA) cycle, fatty acid metabolism, glutamate metabolism, antioxidant defenses and possibly changes in the liver enzyme machinery. Overall, these results highlight the potential of the intra- and extracellular metabolome to study alterations triggered by subtoxic concentrations of MDMA in hepatic cell functions, which represents a more realistic appraisal of early toxicity events posed by exposure to this drug. In addition, these results also revealed some metabolites that may be used as potential biomarkers indicative of early events in the hepatotoxicity induced by MDMA.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 2
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