Induction of glutathione synthesis and conjugation by 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-dihydroxymethamphetamine (HHMA) in human and rat liver cells, including the protective role of some antioxidants.
Irene Antolino-Lobo, Jan Meulenbelt, Jeffrey Molendijk, Sandra M Nijmeijer, Peter Scherpenisse, Martin Van den Berg, Majorie B M Van Duursen
Toxicology November 18, 2011 DOI: 10.1016/j.tox.2011.08.012 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro cell study Peer reviewed |
|---|---|
| Population | Immortalized human liver epithelial THLE-Neo cells and primary rat hepatocytes |
| Interventions | MDMA 3 4-dihydroxymetamphetamine (HHMA) N-acetyl-cysteine (NAC) sulforaphane (SFN) |
| Topics | MDMA |
| Key points | The authors conclude that the MDMA metabolite HHMA is a major contributor to MDMA-mediated hepatotoxicity through its interaction with the glutathione system. They report that N-acetyl-cysteine counteracted MDMA-induced cytotoxicity and restored glutathione levels, suggesting it may be useful in MDMA intoxication, whereas sulforaphane increased cytotoxicity and glutathione depletion and induced PXR, indicating possible drug-drug interactions that warrant caution. |
Abstract
MDMA (3,4-methylenedioxymethamphetamine) metabolism is a major cause of MDMA-mediated hepatotoxicity. In this study the effects of MDMA and its metabolites on the glutathione system were evaluated. Glutathione (GSH/GSSG) levels and gene expression of glutamate cysteine ligase catalytic subunit (GCLC), glutathione-S-transferase (GST) and pregnane X receptor (PXR) were compared in the immortalized human liver epithelial cell line THLE-Neo lacking phase I metabolism and primary rat hepatocytes expressing both phase I and II metabolism. Furthermore, we evaluated the potential protective effects of two antioxidants, N-acetyl-cysteine (NAC) and sulforaphane (SFN) in these cell systems. In THLE-Neo cells, the MDMA metabolite 3,4-dihydroxymetamphetamine (HHMA) significantly decreased cell viability and depleted GSH levels, resulting in an increased expression of GCLC and GST up to 3.4- and 2.2-fold, respectively. In primary rat hepatocytes, cell viability or GSH levels were not significantly affected upon MDMA exposure. GCLC expression levels where not significantly altered either, although GST expression was increased 2.3-fold. NAC counteracted MDMA-induced cytotoxicity and restored GSH levels. Phase II enzyme expression was also reverted. Conversely, SFN increased MDMA-induced cytotoxicity and GSH depletion, while GCLC and GST expression were significantly induced. In addition, PXR expression decreased after HHMA and MDMA exposure, while co-exposure to SFN induced it up to 3.6- and 3.9-fold compared to vehicle-control in the THLE-Neo cells and rat hepatocytes, respectively. Taken together, these data indicate that HHMA is a major factor in the MDMA-mediated hepatotoxicity through interaction with the glutathione system. The results of our study show that for MDMA intoxication the treatment with an antioxidant such as NAC may counteract the potentially hepatotoxicity. However, SFN supplementation should be considered with care because of the indications of possible drug-drug interactions.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 2
- Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug–drug interactions Critical Reviews in Toxicology October 3, 2012
- Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems Journal of Psychopharmacology April 30, 2019
Cites 15
- Human Pharmacology of MDMA Therapeutic Drug Monitoring March 19, 2004
- Metabolism Is Required for the Expression of Ecstasy-Induced Cardiotoxicity in Vitro Chemical Research in Toxicology April 27, 2004
- Enzymic and chemical demethylenation of (methylenedioxy)amphetamine and (methylenedioxy)methamphetamine by rat brain microsomes Chemical Research in Toxicology May 1, 1992
- Non‐linear pharmacokinetics of MDMA (‘ecstasy’) in humans British Journal of Clinical Pharmacology February 1, 2000
- 3,4-methylenedioxymethamphetamine (MDMA) interacts with therapeutic drugs on CYP3A by inhibition of pregnane X receptor (PXR) activation and catalytic enzyme inhibition. Toxicology Letters March 22, 2011
and 10 more in the library