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

描述(申请人提供)：15-脱氧-三角洲-12，14-前列腺素J2(15-d-PGJ2)是一种高活性的环戊烯酮二十烷类化合物，由环氧合酶(COX)衍生的前列腺素D2(PGD2)脱水生成。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还可以由类似PGD2的化合物脱水生成，称为D2-异前列腺素(Isoprostanes，IsoP)，它是由自由基催化的花生四烯酸在氧化应激条件下过氧化而形成的。这是相关的，因为15-d-PGJ2被认为是一种广泛的生物过程的重要介体。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物激活的受体-γ的配基有关。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发挥了重要作用。尽管人们对15-d-PGJ2的生物活性很感兴趣，但15-d-PGJ2在体内形成的程度以及调节其形成的机制尚不清楚。这项拟议研究的总体目标是确定15-d-PGJ2在体内形成的程度，并检查调节其形成的机制。我们假设COX和IsoP通路在体内参与了15-d-PGJ2的形成。为了验证这一假设，我们将开发质谱学方法来测量15-d-PGJ2的主要尿代谢物，作为其内源生产的生物标志物。因此，提出了以下具体目标：一)测定15-d-PGJ2在大鼠体内的代谢去向，鉴定其主要尿代谢物；比较15-d-PGJ2在大鼠和人体内的代谢；检测COX和IsoP通路在体内15-d-PGJ2形成中的作用。15-d-PGJ2在体内通过COX和IsoP途径产生，可能参与参与炎症和氧化损伤的多种生理和病理生理过程。显然，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，给我国带来了巨大的公共卫生负担。在这种背景下，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学中的作用奠定基础。

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.