A series of prostaglandin F 2-like compounds are produced in vivo in humans by a non-cyclooxygenase , free radical-catalyzed mechanism ( eicosanoids / oxidative stress / lipid peroxidation / mass spectrometry )
A series of prostaglandin F 2-like compounds are produced in vivo in humans by a non-cyclooxygenase , free radical-catalyzed mechanism ( eicosanoids / oxidative stress / lipid peroxidation / mass spectrometry )
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通过非环氧合酶、自由基催化机制（类二十烷酸/氧化应激/脂质过氧化/质谱法）在人体内产生一系列前列腺素F 2 样化合物
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通讯作者：
L. Roberts
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作者：
J. Morrow;K. Hill;R. Burk;T. M. Nammour;K. Badr;L. Roberts
越来越多的注意力集中在来自氧的自由基在各种疾病的病理生理学中的作用。自由基诱导的iWury的公认目标之一是脂质过氧化。使用各种方法，我们已经发现，一系列的前列腺素F2样化合物在人体内产生的非环氧合酶机制，涉及自由基催化的花生四烯酸过氧化反应。这些化合物在正常人血浆和尿液中的水平分别为5至40 pg/ml和500至4000 pg/mg肌酸酐。在大鼠中，它们的形成被发现增加多达200倍，与显着的自由基催化的脂质过氧化诱导的四氯化碳和敌草快管理。为了探索这些前列腺素类是否可以发挥生物活性，在大鼠肾脏中检查了通过该机制形成的化合物之一8-表-前列腺素F2 a的作用。外周静脉（5 μ g/kg/min）或肾内（0.5-2.0 μ g/kg/min）输注8-表-前列腺素F2 a导致肾血流量和肾小球滤过率明显平行降低。这些前列腺素类的形成是由自由基催化的，并且它们可以发挥有效的生物活性，这表明这些前列腺素类可能作为氧化损伤的病理生理介质参与。这些化合物的定量也可以提供一种非侵入性的方法来评估人体的氧化状态。这些前列腺素类的形成不依赖于环氧合酶的催化活性，这表明有时使用环氧合酶抑制剂来评估前列腺素在某些病理生理过程中的作用的可靠性可能存在局限性。大量证据表明，主要来自氧的活性自由基在多种疾病的病理生理学中发挥重要作用，包括动脉粥样硬化、缺血-再灌注损伤、炎性疾病、癌症和衰老（1）。氧化损伤的公认目标之一是脂质过氧化。脂肪酸在体外某些条件下的自氧化导致形成类野牡丹素化合物（2-4）。最近，我们发现血浆中含花生四烯酸的脂质在体外容易发生自由基催化的过氧化反应，导致形成一系列前列腺素F2（PGF 2）样化合物（5）。这似乎是一个非常容易的过程。因此，我们探讨了这些前列腺素类也可能在体内产生的类似机制的环氧合酶的催化活性无关。血浆和尿中PGF 2样化合物的分析。通过GC/负离子化学电离和电子电离MS（5）进行TLC纯化后分析PGF 2样化合物。如（5）所述进行催化氢化以及环状硼酸酯衍生物的形成和分析。环氧合酶抑制对PGF 2样化合物内源性产生的影响的评估。在这些研究中雇用了三名人类志愿者。给予以下药物4天：布洛芬（1000 mg，每天4次）、萘普生（1000 mg，每天4次）和吲哚美辛（200 mg，每天4次）。在三名志愿者中，布洛芬给药三次，萘普生一次，吲哚美辛两次。在每个给药期结束时，采集并分析至少4份血浆样本和1-4份尿液样本，并与未给药期间采集的21份血浆样本和7份尿液样本进行比较。自由基诱导的脂质过氧化的动物模型。如所述，通过向缺硒大鼠施用敌草快（19.5 μ mol/kg）和向正常大鼠施用CC 14（2 ml/kg）诱导内源性脂质过氧化（6，7）。8-epi-PGF_（2a）在大鼠肾脏中的生物学效应将8-epiPGF 2a（来自密歇根州卡拉马祖Upjohn的Gordon Bundy的慷慨礼物）注入如所述制备的等容性雄性Munich-Wistar大鼠的颈静脉或左肾（8）。在开始输注后30分钟测量肾小球滤过率和肾血浆流量（8）。
Increasing attention has focused on the role of free radicals derived from oxygen in the pathophysiology of a wide variety of disorders. One of the well-recognized targets of free radical-induced iWury is peroxidation of lipids. Using a variety of approaches, we have found that a series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase mechanism involving free radicalcatalyzed peroxidation of arachidonic acid. Levels of these compounds in normal human plasma and urine range from 5 to 40 pg/ml and 500 to 4000 pg/mg of creatinine, respectively. In rats, their formation was found to increase as much as 200-fold in association with marked free radical-catalyzed lipid peroxidation induced by administration of CCl4 and diquat. To explore whether these prostanoids can exert biological activity, the effects of one of the compounds formed by this mechanism, 8-epi-prostaglandin F2a, was examined in the kidney in the rat. Infusion of 8-epi-prostaglandin F2a into a peripheral vein (5 jig/kg per min) or intrarenally (0.5-2.0 ,ug/kg per min) resulted in marked parallel reductions in renal blood flow and glomerular filtration rate. That the formation of these prostanoids is catalyzed by free radicals and that they can exert potent biological activity suggest that these prostanoids may participate as pathophysiological mediators in oxidant injury. Quantification of these compounds may also provide a noninvasive approach to assess oxidant status in humans. That the formation of these prostanoids occurs independent of the catalytic activity of the cyclooxygenase enzyme suggests that there may be limitations at times regarding the reliability of the use of cyclooxygenase inhibitors to assess the role of prostaglandins in certain pathophysiological processes. Considerable evidence indicates an important role of reactive free radicals derived primarily from oxygen in the pathophysiology of a wide spectrum of disorders including atherosclerosis, ischemia-reperfusion injury, inflammatory disease, cancer, and aging (1). One of the well-recognized targets of oxidative injury is peroxidation of lipids. Autoxidation of fatty acids under certain conditions in vitro results in the formation of prostaglandin-like compounds (2-4). Recently we found that arachidonoyl-containing lipids in plasma readily undergo free radical-catalyzed peroxidation in vitro, resulting in the formation of a series of prostaglandin F2 (PGF2)-like compounds (5). This appeared to be a very facile process. Therefore, we explored the possibility that these prostanoids may also be produced in vivo by a similar mechanism independent of the catalytic activity of the cyclooxygenase enzyme. EXPERIMENTAL PROCEDURES Analysis of PGF2-Like Compounds in Plasma and Urine. PGF2-like compounds were analyzed following TLC purification by GC/negative-ion chemical ionization and electron ionization MS (5). Catalytic hydrogenation and formation and analysis of cyclic boronate derivatives were carried out as described (5). Assessment of the Effect of Cyclooxygenase Inhibition on the Endogenous Production of PGF2-Like Compounds. Three human volunteers were employed in these studies. The following drugs were administered for 4 days: ibuprofen (1000 mg four times a day), naproxen (1000 mg four times a day), and indomethacin (200 mg four times a day). Among the three volunteers, ibuprofen was administered three times, naproxen once, and indomethacin twice. At least 4 plasma samples and 1-4 urine samples were obtained and analyzed at the end of each treatment period and compared to 21 plasma samples and 7 urine samples obtained during periods of no drug treatment. Animal Models of Free Radical-Induced Lipid Peroxidation. Endogenous lipid peroxidation was induced by administration of diquat (19.5 /umol/kg) to Se-deficient rats and CC14 (2 ml/kg) to normal rats, as described (6, 7). Biological Effects of 8-epi-PGF2a in the Rat Kidney. 8-epiPGF2a (a generous gift from Gordon Bundy of Upjohn, Kalamazoo, MI) was infused into the jugular or left renal of euvolemic male Munich-Wistar rats prepared as described (8). Glomerular filtration rate and renal plasma flow were measured 30 min after the initiation of the infusion (8).