| The metabolomics of (+/-)-arecoline 1-oxide in the mouse and its formation by human flavin-containing monooxygenases. | |
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MedLine Citation:
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PMID: 17123469 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Sarbani Giri; Kristopher W Krausz; Jeffrey R Idle; Frank J Gonzalez |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't Date: 2006-10-21 |
Journal Detail:
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Title: Biochemical pharmacology Volume: 73 ISSN: 0006-2952 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2007 Feb |
Date Detail:
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Created Date: 2007-01-10 Completed Date: 2007-04-23 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 561-73 Citation Subset: IM |
Affiliation:
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Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetylcysteine
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chemistry,
urine Administration, Oral Animals 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 Dogs Humans Kinetics Male Mass Spectrometry Metabolic Networks and Pathways* Mice Molecular Structure Nipecotic Acids / chemistry, urine Oxygenases / genetics, metabolism* Piperidines / chemistry, urine Recombinant Proteins / metabolism Stereoisomerism Sulfhydryl Compounds / chemistry, urine Urinalysis / methods |
| Chemical | |
Reg. No./Substance:
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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 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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