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J. Biol. Chem., Vol. 278, Issue 31, 28479-28489, August 1, 2003

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Formation of Prostaglandins E₂ and D₂ via the Isoprostane Pathway

A MECHANISM FOR THE GENERATION OF BIOACTIVE PROSTAGLANDINS INDEPENDENT OF CYCLOOXYGENASE^*

Ling Gao  , William E. Zackert , Justin J. Hasford , Michael E. Danekis , Ginger L. Milne , Catha Remmert , Jeff Reese ¶, Huiyong Yin ||, Hsin-Hsiung Tai **, Sudhansu K. Dey ¶, Ned A. Porter || and Jason D. Morrow   

From the Departments of Medicine, Pharmacology, ^¶Pediatrics, and Chemistry, ^||Vanderbilt University, Nashville, Tennessee 37232 and the ^**College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536

It has heretofore been assumed that the cyclooxygenases (COXs) are solely responsible for peostaglandin (PG) synthesis in vivo. An important structural feature of PGH₂ formed by COX is the trans-configuration of side chains relative to the prostane ring. Previously, we reported that a series of PG-like compounds termed isoprostanes (IsoPs) are formed in vivo in humans from the free radical-catalyzed peroxidation of arachidonate independent of COX. A major difference between these compounds and PGs is that IsoPs are formed from endoperoxide intermediates, the vast majority of which contain side chains that are cis relative to the prostane ring. In addition, unlike the formation of eicosanoids from COX, IsoPs are formed as racemic mixtures because they are generated nonenzymatically. IsoPs containing E- and D-type prostane rings (E₂/D₂-IsoPs) are one class of IsoPs formed, and we have reported previously that one of the major IsoPs generated is 15-E_2t-IsoP (8-iso-PGE₂). Unlike PGE₂, 15-E_2t-IsoP is significantly more unstable in buffered solutions in vitro and undergoes epimerization to PGE₂. Analogously, the D-ring IsoP (15-D_2c-IsoP) would be predicted to rearrange to PGD₂. We now report that compounds identical in all respects to PGE₂ and PGD₂ and their respective enantiomers are generated in vivo via the IsoP pathway, presumably by epimerization of racemic 15-E_2t-IsoP and 15-D_2c-IsoP, respectively. Racemic PGE₂ and PGD₂ were present esterified in phospholipids derived from liver tissue from rats exposed to oxidant stress at levels of 24 ± 16 and 37 ± 12 ng/g of tissue, respectively. In addition, racemic PGs, particularly PGD₂, were present unesterified in urine from normal animals and humans and represented up to 10% of the total PG detected. Levels of racemic PGD₂ increased 35-fold after treatment of rats with carbon tetrachloride to induce oxidant stress. In this setting, PGD₂ and its enantiomer generated by the IsoP pathway represented 30% of the total PGD₂ present in urine. These findings strongly support the contention that a second pathway exists for the formation of bioactive PGs in vivo that is independent of COX.

Received for publication, April 16, 2003 , and in revised form, May 5, 2003.

^* This work was supported in part by National Institutes of Health Grants DK48831, GM42056, CA77839, HD12304, and HL46296. 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.

Recipient of a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research. To whom correspondence should be addressed: Vanderbilt University, 526 RRB, 23rd and Pierce Aves., Nashville, TN 37232-6602. Tel.: 615-343-1124; Fax: 615-322-3669; E-mail: jason.morrow{at}mcmail.vanderbilt.edu.

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