Reduced (+/-)-3,4-methylenedioxymethamphetamine ("Ecstasy") metabolism with cytochrome P450 2D6 inhibitors and pharmacogenetic variants in vitro.
"Ecstasy" [(+/-)-3,4-methylenedioxymethamphetamine or MDMA] is a CNS stimulant, whose use is increasing despite evidence of long-term neurotoxicity. In vitro, the majority of MDMA is demethylenated to (+/-)-3,4-dihydroxymethamphetamine (DHMA) by the polymorphic cytochrome P450 2D6 (CYP2D6). We investigated the demethylenation of MDMA and dextromethorphan (DEX), as a comparison drug, in reconstituted microsomes expressing the variant CYP2D6 alleles (*)2, (*)10, and (*)17, all of which have been linked to decreased enzyme activity. With MDMA, intrinsic clearances (V(max)/K(m)) in CYP2D6.2, CYP2D6.17, and CYP2D6.10 were reduced 15-, 13-, and 135-fold, respectively, compared with wild-type CYP2D6.1. With DEX, intrinsic clearances were reduced by 37-, 51-, and 164-fold, respectively. It was evident that CYP2D6.17 displayed substrate-specific changes in drug affinity (K(m)). Compounds potentially used with MDMA [fluoxetine, paroxetine, (-)-cocaine] demonstrated significant inhibition of MDMA metabolism in both human liver and CYP2D6.1-expressing microsomes. These data demonstrate that individuals possessing the CYP2D6(*)2, (*)17, and, particularly, (*)10 alleles may show significantly reduced MDMA metabolism. These individuals, and those taking CYP2D6 inhibitors, may demonstrate altered acute and/or long-term MDMA-related toxicity.
Ramamoorthy
Yamini
Y
Department of Pharmacology, University of Toronto, Ont., Canada.
Yu
Ai-ming
AM
Suh
Nina
N
Haining
Robert L
RL
Tyndale
Rachel F
RF
Sellers
Edward M
EM
D000483:Alleles; D003042:Cocaine / Q000494:pharmacology; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003915:Dextromethorphan / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006213:Hallucinogens / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000378:metabolism*; D010084:Oxidation-Reduction; D011994:Recombinant Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D003042:Cocaine; D019389:Cytochrome P-450 CYP2D6; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003915:Dextromethorphan; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D006213:Hallucinogens; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D011994:Recombinant Proteins; D017367:Selective Serotonin Reuptake Inhibitors