HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 1, 329-336, January 5, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/1/329    most recent M608975200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yin, H. Articles by Morrow, J. D. Search for Related Content PubMed PubMed Citation Articles by Yin, H. Articles by Morrow, J. D. Social Bookmarking                      What's this?

Urinary Prostaglandin F₂ Is Generated from the Isoprostane Pathway and Not the Cyclooxygenase in Humans^*

Huiyong Yin, Ling Gao, Hsin-Hsiung Tai^¶, Laine J. Murphey, Ned A. Porter, and Jason D. Morrow¹

From the Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Department of Chemistry, Center in Molecular Toxicology, and the Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232 and the Department of Pharmaceutical Sciences, ^¶University of Kentucky, Lexington, Kentucky 40536

Prostaglandins (PGs) derived from the enzymatic oxidation of arachidonic acid by the cyclooxygenases (COXs) are potent lipid mediators involved in human physiology and pathophysiology. Structurally similar compounds, the isoprostanes (IsoPs), are generated from the free radical-catalyzed oxidation of arachidonic acid independent of COX. IsoPs exhibit significant bioactivity and play a role in the pathogenesis of diseases associated with oxidant injury. As one of the major PGs, prostaglandin F₂ (PGF₂) is present in human urine in significant concentrations and is presumed to be derived from COX activity. We determined, however, that levels of putative PGF₂ in urine cannot be suppressed by nonsteroidal anti-inflammatory agents, suggesting that it is generated via another mechanism(s). An important difference between COX-derived PGF₂ and the IsoPs is that the former is an optically pure compound, whereas IsoPs are racemic. Utilizing a rodent model of oxidative stress, we now show that significant amounts of compounds identical in all respects to PGF₂ and its enantiomer, ent-PGF₂, are formed in equal amounts esterified in tissue phospholipids, suggesting that these compounds are derived via the IsoP pathway. Further, employing liquid chromatography/mass spectrometry, the vast majority of putative PGF₂ in human urine is derived from the free radical-initiated peroxidation of arachidonate independent of COX and is composed of PGF₂ and its enantiomer, although the latter compound is 2-fold more abundant. Thus, quantification of urinary PGF₂ actually reflects oxidative stress status as opposed to COX activity. Indeed, levels of this compound are elevated in urine from cigarette smokers and in humans with hypercholesterolemia, two conditions associated with oxidant stress. The elucidation that urinary PGF₂ in humans is derived from the IsoP pathway has implications regarding PG formation and inhibition in vivo.

Received for publication, September 20, 2006 , and in revised form, November 8, 2006.

^* This work was supported by National Institutes of Health Grants DK48831, RR00095, CA77839, HL17921, GM15431, ES00267, P30 ES000267, and ES13125. 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 To whom correspondence should be addressed: Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, 532 RRB, 23rd and Pierce Aves., Nashville, TN 37232-6602. Tel.: 615-343-1124; Fax: 615-322-3669; E-mail: Jason.morrow{at}vanderbilt.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				L. J. Roberts II and G. L. Milne Isoprostanes J. Lipid Res., April 1, 2009; 50(Supplement): S219 - S223. [Abstract] [Full Text] [PDF]

				H. C. Kuiper, C. L. Miranda, J. D. Sowell, and J. F. Stevens Mercapturic Acid Conjugates of 4-Hydroxy-2-nonenal and 4-Oxo-2-nonenal Metabolites Are in Vivo Markers of Oxidative Stress J. Biol. Chem., June 20, 2008; 283(25): 17131 - 17138. [Abstract] [Full Text] [PDF]

				G. L. Milne, H. Yin, and J. D. Morrow Human Biochemistry of the Isoprostane Pathway J. Biol. Chem., June 6, 2008; 283(23): 15533 - 15537. [Full Text] [PDF]