title: Sprague-Dawley rats display metabolism-mediated sex differences in the acute toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy).
abstract: The use of the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has been associated with unexplained deaths. Male humans and rodents are more sensitive to acute toxicity than are females, including a potentially lethal hyperthermia. MDMA is highly metabolized to five main metabolites, by the enzymes CYP1A2 and CYP2D. The major metabolite in rats, 3,4-methylenedioxyamphetamine (MDA), also causes hyperthermia. We postulated that the reported sex difference in rats is due to a sexual dimorphism(s). We therefore determined (1) the LD50 of MDMA and MDA, (2) their hyperthermic effects, (3) the activities of liver CYP1A2 and CYP2D, (4) the liver microsomal metabolism of MDMA and MDA, (5) and the plasma concentrations of MDMA and its metabolites 3 h after giving male and female Sprague-Dawley (SD) rats MDMA (5 mg.kg(-1) sc). The LD50 of MDMA was 2.4-times lower in males than in females. MDMA induced greater hyperthermia (0.9 degrees C) in males. The plasma MDA concentration was 1.3-fold higher in males, as were CYP1A2 activity (twice) and N-demethylation to MDA (3.3-fold), but the plasma MDMA concentration (1.4-fold) and CYP2D activity (1.3-fold) were higher in females. These results suggest that male SD rats are more sensitive to MDMA acute toxicity than are females, probably because their CYP1A2 is more active, leading to higher N-demethylation and plasma MDA concentration. This metabolic pathway could be responsible for the lethality of MDMA, as the LD50 of MDA is the same in both sexes. These data strongly suggest that the toxicity of amphetamine-related drugs largely depends on metabolic differences.
authors: Université Paris Descartes, Faculté de Pharmacie, Paris F-75006, France.
authors: Julien
authors: J
authors: Fonsart
authors: Marie-Claude
authors: MC
authors: Menet
authors: Xavier
authors: X
authors: Declèves
authors: Hervé
authors: H
authors: Galons
authors: Dominique
authors: D
authors: Crété
authors: Marcel
authors: M
authors: Debray
authors: Jean-Michel
authors: JM
authors: Scherrmann
authors: Florence
authors: F
authors: Noble
mesh_terms: D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006213:Hallucinogens / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity*; D007928:Lethal Dose 50; D008297:Male; D008745:Methylation / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics
chemical_list: D006213:Hallucinogens; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D018817:N-Methyl-3,4-methylenedioxyamphetamine