Formation and Metabolism of 15-deoxy-delta-12, 14-prostaglandin J2 in Vivo

描述（由申请人提供）：15-deoxy- δ -12,14-前列腺素J2 （15-d-PGJ2）是一种高活性的环戊烯酮类二十烷酸，由环氧化酶（COX）衍生的前列腺素D2 （PGD2）脱水产生。我们已经获得了支持这一论点的数据。除了COX途径外，15-d-PGJ2还可以通过pgd2样化合物（称为d2 -异前列腺素（IsoPs））的脱水产生，这种化合物是在氧化应激条件下由自由基催化花生四烯酸过氧化反应形成的。这是相关的，因为15-d-PGJ2被认为是多种生物过程的重要介质。其多样的生物活性很大程度上归因于其前列腺环上活性多不饱和羰基部分的存在，该部分是与含硫醇的生物分子（如蛋白质上的谷胱甘肽和半胱氨酸残基）进行Michael加成的底物。15-d-PGJ2已被证明具有抗增殖和促凋亡活性。它的一些活性可能与观察到它是过氧化物酶体增殖激活受体γ的配体有关。此外，据报道，15-d-PGJ2在人类动脉粥样硬化病变中大量存在，并存在于泡沫细胞中，这表明它在调节炎症和凋亡反应中起重要作用。尽管人们对其生物活性非常感兴趣，但15-d-PGJ2在体内形成的程度和调节其形成的机制尚不清楚。本研究的总体目标是确定15-d-PGJ2在体内形成的程度，并研究其形成的调节机制。我们假设COX和IsoP通路都有助于体内15-d-PGJ2的形成。为了验证这一假设，我们将开发质谱方法来测量15-d-PGJ2的主要尿液代谢物，作为其内源性生产的生物标志物。因此，提出了以下具体目标：确定15-d-PGJ2在大鼠体内的代谢命运，并确定其主要尿液代谢物；二)。比较15-d-PGJ2在大鼠和人体内的代谢；和III)。在体内研究COX和IsoP通路对15- d-PGJ2形成的贡献。15-d-PGJ2在体内通过COX和IsoP途径产生，可介导炎症和氧化损伤等多种生理和病理生理过程。很明显，与炎症和/或氧化损伤相关的疾病，如动脉粥样硬化、阿尔茨海默病和癌症，对我们的国家构成了巨大的公共卫生负担。在此背景下，研究15-d-PGJ2的形成和代谢将为了解其在这些疾病和相关疾病的病理生理中的作用奠定基础。

DESCRIPTION (provided by applicant): 15-deoxy-delta-12,14-prostaglandin J2 (15-d-PGJ2) is a highly reactive cyclopentenone eicosanoid generated from the dehydration of cyclooxygenase(COX)-derived prostaglandin D2 (PGD2). We have obtained data supporting the contention that. In addition to the COX pathway, 15-d-PGJ2 can be generated from the dehydration of PGD2-like compounds, termed D2-isoprostanes (IsoPs), which are formed from the free radical-catalyzed peroxidation of arachidonic acid under settings of oxidative stress. This is relevant because 15-d-PGJ2 has been postulated as an important mediator of a wide variety of biological processes. Its diverse bioactivities are largely attributed to the presence of a reactive polyunsaturated carbonyl moiety on its prostane ring that is a substrate for Michael addition with thiol-containing biomolecules, such as glutathione and cysteine residues on proteins. 15-d-PGJ2 has been shown to possess anti-proliferative and pro-apoptotic activity. Some of its activity may relate to the observation that it is a ligand for peroxisome proliferator-activated receptor-gamma. Additionally, 15-d-PGJ2 has been reported to be present in significant amounts in human atherosclerotic lesions and to reside in foam cells, suggesting an important role for it in modulating inflammatory and apoptotic responses. Despite great interest in its bioactivity, the extent to which 15-d-PGJ2 is formed in vivo and the mechanisms that regulate its formation are unclear. The overall goal of the proposed research is to determine the extent to which 15-d-PGJ2 is formed in vivo and examine the mechanisms that regulate it formation. We hypothesize that both the COX and IsoP pathways contribute to the formation of 15-d-PGJ2 in vivo. To test this hypothesis, we will develop mass spectrometric methodologies to measure the major urinary metabolite of 15-d-PGJ2 as a biomarker of its endogenous production. The following specific aims are thus proposed: I.) Determine the metabolic fate of 15-d-PGJ2 in the rat and identify its major urinary metabolite; II.) Compare the metabolism of 15-d-PGJ2 in rats and humans; and III.) Examine the contributions of the COX and IsoP pathways to the formation of 15- d-PGJ2 in vivo. As a result of being generated through the COX and IsoP pathways in vivo, 15-d-PGJ2 may mediate various physiological and pathophysiological processes involved in inflammation and oxidant injury. It is clear that diseases associated with inflammation and/or oxidative injury, such as atherosclerosis, Alzheimer's disease, and cancer, pose a tremendous public health burden on our nation. In this context, studies examining the formation and metabolism of 15-d-PGJ2 will lay the foundation for understanding its role in the pathophysiology of these and related diseases.