title: Acute administration of 3,4-methylenedioxymethamphetamine (MDMA) induces oxidative stress, lipoperoxidation and TNFα-mediated apoptosis in rat liver.
abstract: Liver toxicity is one of the consequences of ecstasy (3,4-methylenedioxymethamphetamine MDMA) abuse and hepatocellular damage is reported after MDMA consumption. Various factors probably play a role in ecstasy-induced hepatotoxicity, namely its metabolism, the increased efflux of neurotransmitters, the oxidation of biogenic amines, and hyperthermia. MDMA undergoes extensive hepatic metabolism that involves the production of reactive metabolites which form adducts with intracellular nucleophilic sites. MDMA-induced-TNF-α can promote multiple mechanisms to initiate apoptosis in hepatocytes, activation of pro-apoptotic (BID, SMAC/DIABLO) and inhibition of anti-apoptotic (NF-κB, Bcl-2) proteins. The aim of the present study was to obtain evidence for the oxidative stress mechanism and apoptosis involved in ecstasy-induced hepatotoxicity in rat liver after a single 20 mg/kg, i.p. MDMA administration. Reduced and oxidized glutathione (GSH and GSSG), ascorbic acid (AA), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and malondialdehyde (MDA), an indicator of lipid peroxidation, were determined in rat liver after 3 and 6h after MDMA treatment. The effect of a single MDMA treatment included decrease of GR and GPx activities (29% and 25%, respectively) and GSH/GSSG ratio (32%) with an increase of MDA (119%) after 3h from ecstasy administration compared to control rats. Liver cytosolic level of AA was increased (32%) after 6 h MDMA treatment. Our results demonstrate a strong positive reaction for TNFα (p<0.001) in hepatocytes and a diffuse apoptotic process in the liver specimens (p<0.001). There was correlation between immunohistochemical results and Western blotting which were quantitatively measured by densitometry, confirming the strong positivity for TNF-α (p<0.001) and NF-κB (p<0.001); weak and intense positivity reactions was confirmed for Bcl-2, SMAC/DIABLO (p<0.001) and BID reactions (p<0.001). The results obtained in the present study suggest that MDMA induces loss of GSH homeostasis, decreases antioxidant enzyme activities, and lipoperoxidation that causes an oxidative stress that accompaines the MDMA-induced apoptosis in liver cells.
authors.affiliation: Pharmacology Unit, Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, via delle Scotte 6, 53100 Siena, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Cerretani
authors.forename: S
authors.initials: S
authors.lastname: Bello
authors.forename: S
authors.initials: S
authors.lastname: Cantatore
authors.forename: A I
authors.initials: AI
authors.lastname: Fiaschi
authors.forename: G
authors.initials: G
authors.lastname: Montefrancesco
authors.forename: M
authors.initials: M
authors.lastname: Neri
authors.forename: C
authors.initials: C
authors.lastname: Pomara
authors.forename: I
authors.initials: I
authors.lastname: Riezzo
authors.forename: C
authors.initials: C
authors.lastname: Fiore
authors.forename: A
authors.initials: A
authors.lastname: Bonsignore
authors.forename: E
authors.initials: E
authors.lastname: Turillazzi
authors.forename: V
authors.initials: V
authors.lastname: Fineschi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D006213:Hallucinogens / Q000008:administration & dosage / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D006213:Hallucinogens; D014409:Tumor Necrosis Factor-alpha; D018817:N-Methyl-3,4-methylenedioxyamphetamine