PT  - JOURNAL ARTICLE
AU  - John R. Cashman
AU  - Yeng N. Xiong
AU  - Lifen Xu
AU  - Aaron Janowsky
TI  - <em>N</em>-Oxygenation of Amphetamine and Methamphetamine by the Human Flavin-Containing Monooxygenase (Form 3): Role in Bioactivation and Detoxication
DP  - 1999 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1251--1260
VI  - 288
IP  - 3
4099  - http://jpet.aspetjournals.org/content/288/3/1251.short
4100  - http://jpet.aspetjournals.org/content/288/3/1251.full
SO  - J Pharmacol Exp Ther1999 Mar 01; 288
AB  - (+)- And (−)-amphetamine and methamphetamine wereN-oxygenated by the cDNA expressed adult human flavin-containing monooxygenase form 3 (FMO3), their corresponding hydroxylamines. Two major polymorphic forms of human FMO3 were studied, and the results suggested preferentialN-oxygenation by only one of the two enzymes. Chemically synthesized (±)-amphetamine hydroxylamine was also a substrate for the human FMO3 and it was converted to phenylpropanone oxime with a stereoselectivity ratio of trans/cis of 5:1. Human FMO3 also N-oxygenated methamphetamine to produce methamphetamine hydroxylamine. Methamphetamine hydroxylamine was alsoN-oxygenated by human FMO3, and the ultimate product observed was phenylpropanone. For amphetamine hydroxylamine, studies of the biochemical mechanism of product formation were consistent with the production of an N,N-dioxygenated intermediate that lead to phenylpropanone oxime. This was supported by the observation that α-deutero (±)-amphetamine hydroxylamine gave an inverse kinetic isotope effect on product formation in the presence of human FMO3. For methamphetamine, the data were consistent with a mechanism of human FMO3-mediated N,N-dioxygenation but the immediate product, a nitrone, rapidly hydrolyzed to phenylpropanone. The pharmacological activity of amphetamine hydroxylamine, phenylpropanone oxime, and methamphetamine hydroxylamine were examined for effects at the human dopamine, serotonin, and norepinephrine transporters. Amphetamine hydroxylamine and methamphetamine hydroxylamine were apparent substrates for the human biogenic amine transporters but phenylpropanone oxime was not. Presumably, phenylpropanone oxime or nitrone formation from amphetamine and methamphetamine, respectively, represents a detoxication process. Because of the potential toxic nature of amphetamine hydroxylamine and methamphetamine hydroxylamine metabolites and the polymorphic nature of N-oxygenation, human FMO3-mediated metabolism of amphetamine or methamphetamine may have clinical consequences. The American Society for Pharmacology and Experimental Therapeutics