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J. Biol. Chem., Vol. 281, Issue 6, 3096-3104, February 10, 2006

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Myeloperoxidase Generates 5-Chlorouracil in Human Atherosclerotic Tissue

A POTENTIAL PATHWAY FOR SOMATIC MUTAGENESIS BY MACROPHAGES^*

Junko Takeshita, Jaeman Byun, Thomas Q. Nhan^¶, David K. Pritchard^¶, Subramaniam Pennathur¹, Steven M. Schwartz^¶, Alan Chait, and Jay W. Heinecke²

From the Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 and the Departments of ^¶Pathology and Medicine, University of Washington, Seattle, Washington 98195

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.

Received for publication, August 22, 2005 , and in revised form, November 14, 2005.

^* This work was supported in part by Grants AG19309, AG02119, P30ES07083, P30DK017047, and PO1HL030086 from the National Institutes of Health and by the Donald W. Reynolds Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a Career Development Award from the Juvenile Diabetes Research Foundation (Grant 2-2003-149).

² To whom correspondence should be addressed: Division of Metabolism, Endocrinology and Nutrition, Box 356426, University of Washington, Seattle, WA 98195. Tel.: 206-543-3470; Fax: 206-685-8346; E-mail: heinecke{at}u.washington.edu.

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