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J. Biol. Chem., Vol. 282, Issue 40, 29114-29121, October 5, 2007

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The Metabolism and Dechlorination of Chlorotyrosine in Vivo^*

Ali R. Mani¹, Silvia Ippolito¹, José C. Moreno, Theo J. Visser, and Kevin P. Moore²

From the Department of Medicine, Royal Free & University College Medical School, University College London, London NW3 2PF, United Kingdom and the Department of Internal Medicine, Erasmus University Medical Center, 3015 GE, Rotterdam, The Netherlands

During inflammation, neutrophil- and monocyte-derived myeloperoxidase catalyzes the formation of hypochlorous acid, which can chlorinate tyrosine residues in proteins to form chlorotyrosine. However, little is known of the metabolism and disposition of chlorotyrosine in vivo. Following infusion of deuterium-labeled [D₄]chlorotyrosine into Sprague-Dawley rats, the major urinary metabolites were identified by mass spectrometry. 3-Chloro-4-hydroxyphenylacetic acid was identified as the major chlorinated metabolite of chlorotyrosine and accounted for 3.6 ± 0.3% of infused [D₄]chlorotyrosine. The striking observation was that 40% (39 ± 1%) of infused [D₄]chlorotyrosine was dechlorinated and excreted in the urine as deuterated 4-hydroxyphenylacetic acid, a major metabolite of tyrosine. 1.1 ± 0.1% of infused [D₄]chlorotyrosine was excreted as [D₄]tyrosine. To determine whether protein-bound chlorotyrosine could undergo dechlorination, chlorinated albumin was incubated with liver homogenate from mutant rats, which did not synthesize albumin. There was 20% decrease in the chlorotyrosine content over 1 h. This study is the first to describe the dechlorination of chlorotyrosine as the major metabolic pathway to eliminate this modified amino acid in vivo.

Received for publication, May 23, 2007 , and in revised form, August 7, 2007.

^* This work was supported by the Wellcome Trust, United Kingdom. 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Medicine, Royal Free & University College Medical School, Rowland Hill St., London, NW3 2PF, UK. Tel.: 44-207-433-2878; Fax: 44-207-433-2871; E-mail: kmoore{at}medsch.ucl.ac.uk.

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