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J. Biol. Chem., Vol. 278, Issue 27, 24449-24460, July 4, 2003

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Urinary Metabolites of Leukotriene B₄ in the Human Subject^*

Karin A. Zemski Berry, Pierre Borgeat , Jean Gosselin , Louis Flamand  and Robert C. Murphy 

From the Department of Pediatrics, Division of Cell Biology, National Jewish Medical and Research Center, Denver, Colorado 80206, Virocell Inc., Quebec City, Quebec G1V 2L2, and Centre de Recherche en Rheumatologie et Immunologie, CHUL Research Center, Quebec City, Quebec G1V 4G2, Canada

Leukotriene B₄ (LTB₄) is a potent chemoattractant for neutrophils and is thought to play a role in a variety of inflammatory responses in humans. The metabolism of LTB₄ in vitro is complex with several competing pathways of biotransformation, but metabolism in vivo, especially for normal human subjects, is poorly understood. As part of a Phase I Clinical Trial of human tolerance to LTB₄, four human subjects were injected with 150 nmol/kg LTB₄ with one additional subject as placebo control. The urine of the subjects was collected in two separate pools (0–6 and 7–24 h), and aliquots from these urine collections were analyzed using high performance liquid chromatography, UV spectroscopy, and negative ion electrospray ionization tandem mass spectrometry for metabolites of LTB₄. In the current investigation, 11 different metabolites of LTB₄ were identified in the urine from those subjects injected with LTB₄, and none were present in the urine from the placebo-injected subject. The unconjugated LTB₄ metabolites found in urine were structurally characterized as 18-carboxy-LTB₄, 10,11-dihydro-18-carboxy-LTB₄, 20-carboxy-LTB₄, and 10,11-dihydro-20-carboxy-LTB₄. Several glucuronide-conjugated metabolites of LTB₄ were characterized including 17-, 18-, 19-, and 20-hydroxy-LTB₄, 10-hydroxy-4,6,12-octadecatrienoic acid, LTB₄, and 10,11-dihydro-LTB₄. The amount of LTB₄ glucuronide (16.7–29.4 pmol/ml) and 20-carboxy-LTB₄ (18.9–30.6 pmol/ml) present in the urine of subjects injected with LTB₄ was determined using an isotope dilution mass spectrometric assay before and after treatment of the urine samples with -glucuronidase. The urinary metabolites of LTB₄ identified in this investigation were excreted in low amounts, yet it is possible that one or more of these metabolites could be used to assess LTB₄ biosynthesis following activation of the 5-lipoxygenase pathway in vivo.

Received for publication, January 27, 2003 , and in revised form, April 21, 2003.

^* This work was supported in part by National Institutes of Health Grant HL25785 and the James F. Murray Postdoctoral Fellowship Grant KZB from National Jewish Medical and Research Center. 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.

To whom correspondence should be addressed: National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. Tel.: 303-398-1849; Fax: 303-398-1694; E-mail: murphyr{at}njc.org.

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