Document Detail


Myeloperoxidase generates 5-chlorouracil in human atherosclerotic tissue: a potential pathway for somatic mutagenesis by macrophages.
MedLine Citation:
PMID:  16326702     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Somatic mutations induced by oxidative damage of DNA might play important roles in atherogenesis. However, the underlying mechanisms remain poorly understood. Myeloperoxidase, a heme protein expressed by select populations of artery wall macrophages, initiates one potentially mutagenic pathway by generating hypochlorous acid. This potent chlorinating agent reacts rapidly with primary amines to yield long-lived, selectively reactive N-chloramines. In the current studies, we demonstrate that myeloperoxidase produced by human macrophages differentiated in the presence of granulocyte macrophage colony-stimulating factor generates 5-chlorouracil, a mutagenic thymine analog. The primary amine taurine fails to block the reaction, suggesting that N-haloamines produced by macrophages might oxidize uracil. Model system studies demonstrated that N-chloramines convert uracil to 5-chlorouracil. Interestingly, the tertiary amine nicotine dramatically enhances uracil chlorination, suggesting that cigarette smoke might promote nucleobase oxidation by N-chloramines. To look for evidence that myeloperoxidase promotes uracil oxidation in vivo, we measured 5-chlorouracil levels in human aortic tissue, using isotope dilution gas chromatography-mass spectrometry. The level of 5-chlorouracil was 10-fold higher in atherosclerotic aortic tissue obtained during vascular surgery than in normal aortic tissue, suggesting that halogenated nucleobases produced by macrophages might contribute to atherogenesis. Because 5-chlorouracil can be incorporated into nuclear DNA, our observations raise the possibility that halogenation reactions initiated by phagocytes provide one pathway for mutagenesis, phenotypic modulation, and cytotoxicity during atherogenesis.
Authors:
Junko Takeshita; Jaeman Byun; Thomas Q Nhan; David K Pritchard; Subramaniam Pennathur; Steven M Schwartz; Alan Chait; Jay W Heinecke
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2005-12-01
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  281     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-02-07     Completed Date:  2006-04-11     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3096-104     Citation Subset:  IM    
Affiliation:
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
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MeSH Terms
Descriptor/Qualifier:
Antioxidants / chemistry
Aorta / pathology
Atherosclerosis / metabolism*
Chlorides / chemistry
Chromatography, High Pressure Liquid
DNA / metabolism
Dose-Response Relationship, Drug
Gas Chromatography-Mass Spectrometry
Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
Heme / chemistry
Humans
Hydrogen-Ion Concentration
Macrophages / metabolism*
Models, Chemical
Monocytes / metabolism
Mutagenesis
Mutation
Nicotine / chemistry
Peroxidase / metabolism*
Phenotype
Temperature
Thymine / chemistry
Time Factors
Uracil / analogs & derivatives*,  chemistry,  metabolism
Grant Support
ID/Acronym/Agency:
AG02119/AG/NIA NIH HHS; AG19309/AG/NIA NIH HHS; P01HL030086/HL/NHLBI NIH HHS; P30DK017047/DK/NIDDK NIH HHS; P30ES07083/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Antioxidants; 0/Chlorides; 14875-96-8/Heme; 1820-81-1/5-chlorouracil; 54-11-5/Nicotine; 65-71-4/Thymine; 66-22-8/Uracil; 83869-56-1/Granulocyte-Macrophage Colony-Stimulating Factor; 9007-49-2/DNA; EC 1.11.1.7/Peroxidase

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


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