Acute toxicity of 3,4-methylenedioxymethamphetamine (MDMA) in Sprague-Dawley and Dark Agouti rats.
Ingestion of MDMA ("ecstasy") by humans can cause acute toxicity manifested by hyperthermia and death. Demethylenation of MDMA is catalyzed by cytochrome P-450 2D6 (CYP2D6) and cytochrome P-450 2D1 (CYP2D1) in humans and rats, respectively, and is polymorphically expressed. It has been proposed that CYP2D6 deficiency may account for the unexplained toxicity of MDMA. The female Dark Agouti rat is deficient in CYP2D1, and serves as a model for the human poor metabolizer. We investigated thermogenic and locomotor actions of MDMA in adult female Sprague-Dawley (CYP2D1 replete) and Dark Agouti rats. MDMA (2, 5, and 10 mg/kg) and saline were injected subcutaneously at ambient temperatures of 22 and 31 degrees C. There was no difference in core temperature responses between the two rat strains. Hypothermia occurred in the first 30 min and temperature elevation thereafter. MDMA increased locomotor activity in Sprague-Dawley but not in Dark Agouti rats. However, MDMA had pronounced lethal effects at 31 degrees C ambient in the Dark Agouti rats only. We conclude that the poor metaboliser phenotype may predispose to lethality, but the mechanism is as yet unknown.
Malpass
A
A
Department of Clinical & Experimental Pharmacology, University of Adelaide, SA, Australia.
White
J M
JM
Irvine
R J
RJ
Somogyi
A A
AA
Bochner
F
F
D000429:Alcohol Oxidoreductases; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001833:Body Temperature Regulation / Q000187:drug effects; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D005260:Female; D006213:Hallucinogens / Q000378:metabolism / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D006213:Hallucinogens; D003577:Cytochrome P-450 Enzyme System; D000429:Alcohol Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; C504568:Cyp2d1 protein, rat; D019389:Cytochrome P-450 CYP2D6; D000072467:Cytochrome P450 Family 2; D018817:N-Methyl-3,4-methylenedioxyamphetamine