Document Detail

The metabolomics of (+/-)-arecoline 1-oxide in the mouse and its formation by human flavin-containing monooxygenases.
MedLine Citation:
PMID:  17123469     Owner:  NLM     Status:  MEDLINE    
The alkaloid arecoline is a main constituent of areca nuts that are chewed by approximately 600 million persons worldwide. A principal metabolite of arecoline is arecoline 1-oxide whose metabolism has been poorly studied. To redress this, synthetic (+/-)-arecoline 1-oxide was administered to mice (20mg/kg p.o.) and a metabolomic study performed on 0-12h urine using ultra-performance liquid chromatography-coupled time-of-flight mass spectrometry (UPLC-TOFMS) with multivariate data analysis. A total of 16 mass/retention time pairs yielded 13 metabolites of (+/-)-arecoline 1-oxide, most of them novel. Identity of metabolites was confirmed by tandem mass spectrometry. The principal pathways of metabolism of (+/-)-arecoline 1-oxide were mercapturic acid formation, with catabolism to mercaptan and methylmercaptan metabolites, apparent CC double-bond reduction, carboxylic acid reduction to the aldehyde (a novel pathway in mammals), N-oxide reduction, and de-esterification. Relative percentages of metabolites were determined directly from the metabolomic data. Approximately, 50% of the urinary metabolites corresponded to unchanged (+/-)-arecoline 1-oxide, 25% to other N-oxide metabolites, while approximately, 30% corresponded to mercapturic acids or their metabolites. Many metabolites, principally mercapturic acids and their derivatives, were excreted as diastereomers that could be resolved by UPLC-TOFMS. Arecoline was converted to arecoline 1-oxide in vitro by human flavin-containing monooxygenases FMO1 (K(M): 13.6+/-4.9muM; V(MAX): 0.114+/-0.01nmolmin(-1)microg(-1) protein) and FMO3 (K(M): 44.5+/-8.0microM; V(MAX): 0.014+/-0.001nmolmin(-1)microg(-1) protein), but not by FMO5 or any of 11 human cytochromes P450. This report underscores the power of metabolomics in drug metabolite mining.
Sarbani Giri; Kristopher W Krausz; Jeffrey R Idle; Frank J Gonzalez
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2006-10-21
Journal Detail:
Title:  Biochemical pharmacology     Volume:  73     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-01-10     Completed Date:  2007-04-23     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  561-73     Citation Subset:  IM    
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
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MeSH Terms
Acetylcysteine / chemistry,  urine
Administration, Oral
Arecoline / administration & dosage,  analogs & derivatives,  chemistry,  metabolism*,  urine
Chromatography, Liquid
Cyclic N-Oxides / administration & dosage,  chemistry,  metabolism,  urine
Cytochrome P-450 Enzyme System / genetics,  metabolism
Mass Spectrometry
Metabolic Networks and Pathways*
Molecular Structure
Nipecotic Acids / chemistry,  urine
Oxygenases / genetics,  metabolism*
Piperidines / chemistry,  urine
Recombinant Proteins / metabolism
Sulfhydryl Compounds / chemistry,  urine
Urinalysis / methods
Reg. No./Substance:
0/1-methyl-3,4-dehydropiperidine-3-carboxaldehyde; 0/1-methylnipecotic acid 1-oxide methyl ester; 0/4-mercapto-1-methylnipecotic acid methyl ester; 0/Cyclic N-Oxides; 0/Nipecotic Acids; 0/Piperidines; 0/Recombinant Proteins; 0/Sulfhydryl Compounds; 0/arecoline 1-oxide; 499-04-7/arecaidine; 616-91-1/Acetylcysteine; 63-75-2/Arecoline; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.13.-/Oxygenases; EC monooxygenase (N-oxide forming)

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