Flavin-containing monooxygenase 1-catalysed N,N-dimethylamphetamine N-oxidation

Abstract

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 mu M, V(max) of 7.59 nmol min(-1) mg(-1) protein, and intrinsic clearance of 171 mu l 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.