Novel Pathways of Eicosanoid Metabolism

前列腺素和其他类二十烷酸衍生自花生四烯酸的环氧合酶、脂氧合酶和细胞色素P450氧化。类二十烷酸作为重要的脂质自泌体（局部激素），可发出信号并调节炎症、发热、疼痛和其他生理和病理生理过程。在大多数情况下，由于体内类花生酸和其他类花生酸的短暂性质，无法在其形成部位对其进行直接定量测定。相反，尿代谢产物已被确立为生理和病理生理事件期间类花生酸形成的方便、可靠和非侵入性标记物。同样，这些标记物用于评估抗炎药物和用于调节其生物合成的其他药物的效果和功效。在这里，我们将测试的假设，前列腺素D2（PGD 2），当形成异常高的数额，部分代谢为11-脱氢血栓烷B2（11 d-TxB 2）。该假设基于对已发表数据和初步研究的重新解释，这些数据和初步研究表明，在小鼠中，PGD 2、PGD-M和11 d-TxB 2的尿液代谢产物以及标记的PGD 2代谢为标记的11 d-TxB 2的代谢产物平行形成。假设相同的代谢途径参与其他类二十烷酸的代谢，包括PGE 2和15-脱氧-β-PGJ 2。我们将在三个具体目标中检验这一假设。在12，14目的1中，我们将在PGD 2形成增加的人体模型中分析尿代谢产物PGD-M、11 d-TxB 2和2，3-dinor-TxB 2形成的时间过程。在具体目标2中，我们将使用药理学和遗传学小鼠模型来提供PGD 2转化为11 d-TxB 2的机制分析。在具体目标3中，我们将使用重组酶和肝组织组分来鉴定参与新代谢途径的酶。总之，这些研究将导致重新评估尿液代谢产物的效用，用于定量分析其母体胡萝卜素和类花生酸。这些标记物在抗血小板治疗评估中的有用性具有直接的临床和翻译相关性。

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.