Document Detail


N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication.
MedLine Citation:
PMID:  10027866     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
(+)- And (-)-amphetamine and methamphetamine were N-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 preferential N-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 also N-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 alpha-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.
Authors:
J R Cashman; Y N Xiong; L Xu; A Janowsky
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  288     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  1999 Mar 
Date Detail:
Created Date:  1999-04-01     Completed Date:  1999-04-01     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1251-60     Citation Subset:  IM    
Affiliation:
Human BioMolecular Research Institute, San Diego, California, USA. ledcash@aol.com
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MeSH Terms
Descriptor/Qualifier:
Amphetamine / metabolism*,  pharmacology
Amphetamines*
Humans
Hydroxylamines / metabolism,  pharmacology
Methamphetamine / analogs & derivatives,  metabolism*,  pharmacology
Oxidation-Reduction
Oxygenases / metabolism*
Receptors, Biogenic Amine / drug effects
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
DA 00269/DA/NIDA NIH HHS; DA 11547/DA/NIDA NIH HHS; GM 36426/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Amphetamines; 0/Hydroxylamines; 0/Receptors, Biogenic Amine; 0/amphetamine hydroxylamine; 0/methamphetamine hydroxylamine; 300-62-9/Amphetamine; 537-46-2/Methamphetamine; EC 1.13.-/Oxygenases; EC 1.14.13.8/dimethylaniline monooxygenase (N-oxide forming)

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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