| Extensive metabolic activation of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in smokers. | |
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MedLine Citation:
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PMID: 18628430 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent lung carcinogen present in both unburned tobacco and cigarette smoke. The sum of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides, referred to as total NNAL, is an established urinary biomarker of human NNK uptake. Metabolic activation of NNK to DNA adducts proceeds via alpha-hydroxylation pathways, and 4-oxo-4-(3-pyridyl)butanoic acid (keto acid) and 4-hydroxy-4-(3-pyridyl)butanoic acid (hydroxy acid) are the principal end products of these pathways in rodents and primates. The purpose of this study was to determine NNK metabolic activation in smokers, as measured by the sum of keto acid and hydroxy acid, relative to total NNAL. To specifically identify NNK-derived keto acid and hydroxy acid, which are also formed from nicotine, we added [pyridine-D(4)]NNK to cigarettes that were originally low in NNK, and measured the deuterium-labeled metabolites in the urine of people who smoked these cigarettes. The total amount of [pyridine-D(4)]keto acid plus [pyridine-D(4)]hydroxy acid averaged 4.00 +/- 2.49 nmol/24 h, whereas the average amount of total [pyridine-D(4)]NNAL was 0.511 +/- 0.368 nmol/24 h. The results of this study show for the first time that NNK metabolic activation is a quantitatively significant pathway in smokers, accounting for approximately 86% of total urinary excretion of NNK metabolites. The large interindividual variation in the excreted [pyridine-D(4)]keto acid and [pyridine-D(4)]hydroxy acid among 20 smokers strongly supports our hypothesis that some smokers activate NNK more extensively than others and that the ratio between biomarkers of metabolic activation and detoxification at a given dose of NNK could be a potential indicator of cancer risk. |
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Authors:
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Irina Stepanov; Pramod Upadhyaya; Steven G Carmella; Rachel Feuer; Joni Jensen; Dorothy K Hatsukami; Stephen S Hecht |
Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Volume: 17 ISSN: 1055-9965 ISO Abbreviation: Cancer Epidemiol. Biomarkers Prev. Publication Date: 2008 Jul |
Date Detail:
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Created Date: 2008-07-16 Completed Date: 2008-11-25 Revised Date: 2013-06-05 |
Medline Journal Info:
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Nlm Unique ID: 9200608 Medline TA: Cancer Epidemiol Biomarkers Prev Country: United States |
Other Details:
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Languages: eng Pagination: 1764-73 Citation Subset: IM |
Affiliation:
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The Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. stepa011@umn.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adult Biotransformation Carcinogens / analysis, metabolism* Female Humans Incidence Lung Neoplasms / epidemiology*, metabolism Male Middle Aged Nitrosamines / analysis, urine* Risk Factors Smoking / epidemiology, urine* Tobacco / chemistry United States / epidemiology Young Adult |
| Grant Support | |
ID/Acronym/Agency:
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CA 81301/CA/NCI NIH HHS; R01 CA081301-05/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Carcinogens; 0/Nitrosamines; 64091-91-4/4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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