Document Detail


Extensive metabolic activation of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in smokers.
MedLine Citation:
PMID:  18628430     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Irina Stepanov; Pramod Upadhyaya; Steven G Carmella; Rachel Feuer; Joni Jensen; Dorothy K Hatsukami; Stephen S Hecht
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
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:
Created Date:  2008-07-16     Completed Date:  2008-11-25     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  9200608     Medline TA:  Cancer Epidemiol Biomarkers Prev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1764-73     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
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:
CA 81301/CA/NCI NIH HHS; R01 CA081301/CA/NCI NIH HHS; R01 CA081301-05/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Carcinogens; 0/Nitrosamines; 64091-91-4/4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
Comments/Corrections

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