THE DEMETHYLENATION OF METHYLENEDIOXYMETHAMPHETAMINE (ECSTASY) BY DEBRISOQUINE HYDROXYLASE (CYP2D6)

The metabolism of methylenedioxymethamphetamine (MDMA, ''ecstasy'') was examined in a microsomal preparation of the yeast Saccharomyces cerevisiae expressing human debrisoquine hydroxylase, CYP2D6. Only one product, dihydroxymethylamphetamine (DHMA), was detected in the incubation mixture, and this product accounted for all of the substrate consumption at low concentration (10 mu M). Mean +/- SD values of apparent K-m(mu M) and V-max (nmol/min per nmol P450) for the demethylenation of (+) and (-)-MDMA at low concentrations (1-1000 mu M) were 1.72, 0.12 and 6.45, 0.10 and 2.90, 0.10 and 7.61, 0.06, respectively. At high concentrations (>1000 mu M) substrate inhibition was noted, with K-i values of 14.2 and 28.2 mM, respectively, for the (+) and (-) enantiomers. Incubation of MDMA isomers with human liver microsomes indicated that their demethylenation is deficient in the poor metabolizer phenotype. Thus, MDMA is converted to the catecholamine DHMA by CYP2D6, and this may give rise to genetically-determined differences in toxicity.