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 μM, V_max of 7.59 nmol min⁻¹ mg⁻¹ protein, and intrinsic clearance of 171 μl 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.

Keywords::

• N,N-dimethylamphetamine (DMA)
• flavin-containing monooxygenase
• N-oxidation
• N,N-dimethylamphetamine N-oxide (DMANO)

Acknowledgement

Declaration of interest: This work was supported in part by the grant (2V01440) from Korea Institute of Science and Technology and in part by the grant (M10640010000-06N4001-00100) from National R&D program of Ministry of Education, Science and Technology (MEST) and Korea Science and Engineering Foundation (KOSEF).