Document Detail


The toxicity of N-methyl-alpha-methyldopamine to freshly isolated rat hepatocytes is prevented by ascorbic acid and N-acetylcysteine.
MedLine Citation:
PMID:  15212815     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In the past decade, clinical evidence has increasingly shown that the liver is a target organ for 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") toxicity. The aims of the present in vitro study were: (1) to evaluate and compare the hepatotoxic effects of MDMA and one of its main metabolites, N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and (2) to investigate the ability of antioxidants, namely ascorbic acid and N-acetyl-L-cysteine (NAC), to prevent N-Me-alpha-MeDA-induced toxic injury, using freshly isolated rat hepatocytes. Cell suspensions were incubated with MDMA or N-Me-alpha-MeDA in the final concentrations of 0.1, 0.2, 0.4, 0.8, and 1.6 mM for 3 h. To evaluate the potential protective effects of antioxidants, cells were preincubated with ascorbic acid in the final concentrations of 0.1 and 0.5 mM, or NAC in the final concentrations of 0.1 and 1 mM for 15 min before treatment with 1.6 mM N-Me-alpha-MeDA for 3 h (throughout this incubation period the cells were exposed to both compounds). The toxic effects were evaluated by measuring the cell viability, glutathione (GSH) and glutathione disulfide (GSSG), ATP, and the cellular activities of GSH peroxidase (GPX), GSSG reductase (GR), and GSH S-transferase (GST). MDMA induced a concentration- and time-dependent GSH depletion, but had a negligible effect on cell viability, ATP levels, or on the activities of GR, GPX, and GST. In contrast, N-Me-alpha-MeDA was shown to induce not only a concentration- and time-dependent depletion of GSH, but also a depletion of ATP levels accompanied by a loss in cell viability, and decreases in the antioxidant enzyme activities. For both compounds, GSH depletion was not accompanied by increases in GSSG levels, which seems to indicate GSH depletion by adduct formation. Importantly, the presence of ascorbic acid (0.5 mM) or NAC (1 mM) prevented cell death and GSH depletion induced by N-Me-alpha-MeDA. The results provide evidence that MDMA and its metabolite N-Me-alpha-MeDA induce toxicity to freshly isolated rat hepatocytes. Oxidative stress may play a major role in N-Me-alpha-MeDA-induced hepatic toxicity since antioxidant defense systems are impaired and administration of antioxidants prevented N-Me-alpha-MeDA toxicity.
Authors:
Márcia Carvalho; Fernando Remião; Nuno Milhazes; Fernanda Borges; Eduarda Fernandes; Félix Carvalho; Maria Lourdes Bastos
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Toxicology     Volume:  200     ISSN:  0300-483X     ISO Abbreviation:  Toxicology     Publication Date:  2004 Aug 
Date Detail:
Created Date:  2004-06-23     Completed Date:  2004-08-03     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0361055     Medline TA:  Toxicology     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  193-203     Citation Subset:  IM    
Affiliation:
REQUIMTE, Serviço de Toxicologia, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha 164, 4099/030, Portugal. marciacarvalho@ff.up.pt
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MeSH Terms
Descriptor/Qualifier:
Acetylcysteine / pharmacology*
Adenosine Triphosphate / metabolism
Animals
Antioxidants / pharmacology*
Ascorbic Acid / pharmacology*
Cell Separation
Cell Survival / drug effects
Chromatography, High Pressure Liquid
Deoxyepinephrine / analogs & derivatives*,  antagonists & inhibitors*,  toxicity*
Free Radical Scavengers / pharmacology*
Glutathione / metabolism
Glutathione Peroxidase / metabolism
Glutathione Reductase / metabolism
Glutathione Transferase / metabolism
Hallucinogens / antagonists & inhibitors,  toxicity
Hepatocytes / drug effects*,  enzymology
Male
N-Methyl-3,4-methylenedioxyamphetamine / antagonists & inhibitors,  toxicity
Rats
Spectrophotometry, Ultraviolet
Chemical
Reg. No./Substance:
0/Antioxidants; 0/Free Radical Scavengers; 0/Hallucinogens; 42542-10-9/N-Methyl-3,4-methylenedioxyamphetamine; 50-81-7/Ascorbic Acid; 501-15-5/Deoxyepinephrine; 555-64-6/alpha-methyldopamine; 56-65-5/Adenosine Triphosphate; 616-91-1/Acetylcysteine; 70-18-8/Glutathione; EC 1.11.1.9/Glutathione Peroxidase; EC 1.8.1.7/Glutathione Reductase; EC 2.5.1.18/Glutathione Transferase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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