Novel Pathways of Eicosanoid Metabolism

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Prostaglandins and other eicosanoids are derived from cyclooxygenase, lipoxygenase, and cytochrome P450 oxygenation of arachidonic acid. Eicosanoids serve as important lipid autacoids (local hormones) to signal and regulate inflammation, fever, pain, and other physiological and pathophysiological processes. The fleeting nature of prostaglandins and other eicosanoids in vivo precludes in most cases their direct quantitative measurement at the sites of their formation. Instead, urinary metabolites have been established as convenient, reliable, and non-invasive markers for the formation of eicosanoids during physiological and pathophysiological events. Likewise, these markers are used to assess the effects and efficacy of anti-inflammatory drugs and other medications used to modulate their biosynthesis. Here, we will test the hypothesis that prostaglandin D2 (PGD2), when formed in unusually high amounts, is metabolized in part to 11- dehydro-thromboxane B2 (11d-TxB2). This hypothesis is based on re-interpretation of published data and preliminary studies that show parallel formation of a urinary metabolite of PGD2, PGD- M, and 11d-TxB2, and metabolism of labeled PGD2 to labeled 11d-TxB2 in mice. The same metabolic pathway is hypothesized to be involved in the metabolism of other eicosanoids, including PGE2 and 15-deoxy-∆ -PGJ2. We will test the hypothesis in three specific aims. In 12,14 aim 1 we will analyze the time course of formation of the urinary metabolites PGD-M, 11d-TxB2, and 2,3-dinor-TxB2 in human models of increased formation of PGD2. In specific aim 2 we will use pharmacologic and genetic mouse models to provide a mechanistic analysis of the transformation of PGD2 to 11d-TxB2. In specific aim 3 we will use recombinant enzymes and liver tissue fractions to identify the enzyme(s) involved in the novel metabolic pathway. Together, these studies will lead to a re-evaluation of the utility of urinary metabolites for the quantitative analysis of their parent prostaglandins and eicosanoids. There is immediate clinical and translational relevance for the usefulness of these markers in the assessment of anti-platelet therapy.