Gt. Tucker et al., THE DEMETHYLENATION OF METHYLENEDIOXYMETHAMPHETAMINE (ECSTASY) BY DEBRISOQUINE HYDROXYLASE (CYP2D6), Biochemical pharmacology, 47(7), 1994, pp. 1151-1156
The metabolism of methylenedioxymethamphetamine (MDMA, ''ecstasy'') wa
s examined in a microsomal preparation of the yeast Saccharomyces cere
visiae expressing human debrisoquine hydroxylase, CYP2D6. Only one pro
duct, dihydroxymethylamphetamine (DHMA), was detected in the incubatio
n mixture, and this product accounted for all of the substrate consump
tion 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 a
nd 6.45, 0.10 and 2.90, 0.10 and 7.61, 0.06, respectively. At high con
centrations (>1000 mu M) substrate inhibition was noted, with K-i valu
es 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.