Flavin-containing monooxygenase 1-catalysed N,N-dimethylamphetamine N-oxidation.
N,N-dimethylamphetamine (DMA) is a methamphetamine analogue known to be a weaker central nervous system stimulant than methamphetamine. Although a major metabolite of DMA is known to be DMA N-oxide (DMANO), which may be catalysed by flavin-containing monooxygenase (FMO), the specific enzyme(s) involved in this biotransformation has not been identified. In this study, the specific enzyme(s) involved with DMA N-oxidation was characterized by several assays. When DMA was incubated with different human recombinant drug-metabolizing enzymes, including FMOs and cytochrome P450s (CYPs), the formation of DMANO by FMO1 was the most predominant. The Michaelis-Menten kinetic constants for DMA N-oxidation by FMO1 were: K(m) of 44.5 microM, V(max) of 7.59 nmol min(-1) mg(-1) protein, and intrinsic clearance of 171 microl min(-1) mg(-1) protein, which was about twelve-fold higher than that by FMO3. Imipramine, an FMO1-specific inhibitor, selectively inhibited DMA N-oxidation. The resulting data showed that DMA N-oxidation is mainly mediated by FMO1.
Lee
S K
SK
Korea Institute of Science and Technology, Seoul, Republic of Korea.
Kang
M J
MJ
Jin
C
C
In
M K
MK
Kim
D-H
DH
Yoo
H H
HH
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D007700:Kinetics; D013058:Mass Spectrometry; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D018759:Adrenergic Uptake Inhibitors; D008694:Methamphetamine; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C003714:dimethylamphetamine; D007099:Imipramine