CLINICAL PHARMACOLOGY OF LIPID PEROXIDATION AND ANTIOXIDANT AGENTS

脂质过氧化和抗氧化剂的临床药理学

• 批准号: 6217822
• 负责人: L Jackson Roberts, II
• 金额: $ 22.59万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6217822
• 关键词: Macaca mulatta; antioxidants; arachidonate; atherosclerosis; biomarker; carotene; clinical research; combination chemotherapy; diet therapy; dietary supplements; dosage; drug interactions; human subject; human therapy evaluation; hypercholesterolemia; hyperlipidemia; laboratory mouse; lipoxygenase; metabolism disorder chemotherapy; nutrition related tag; oxidative stress; peroxidation; prostaglandin F; tocopherols; urinalysis

Free radicals have been implicated in an increasing large number of human diseases. Recently we discovered a series of prostaglandin F2-like compounds, termed F2-Isoprostanes (F2-Isop) that are produced independently of the cyclooxygenase enzyme by free radical catalyzed peroxidation of arachidonic acid. F2-Isop['s are formed in situ esterified to phospholipids and released preformed. We have accumulated considerable evidence indicating that measurement of F2-Isop represents an important advance in our ability to assess oxidative stress status in humans. One study is proposed to enhance our ability to assess endogenous production of F2Isop's by measuring a urinary metabolite of the F2-Isop, 8- iso-PGF2alpha. Toward this goal, we plan to determine the metabolic fate of 8-iso-PGF2alpha in the monkey as a basis for the future development of a mass spectrometric assay for a urinary metabolite of 8-iso-PGF2alpha. One of major areas under consideration for human trials of antioxidant therapy with vitamin C, vitamin E, and beta-carotene is in the prevention of atherosclerosis. However, the clinical pharmacology of these agents has not been defined. We have found that patients with hyperlipidemia, have elevated levels of P2-Isop's esterified to plasma lipids. Thus, a study is proposed to establish the dose-dependent effects of these agents given singly and in combination in patients with hyperlipidemia. An impressive amount of evidence has suggested that oxidation of LDL is a key event in atherogenesis that converts LDL to a form that is taken up by macrophages, leading to foam cell formation. In cholesterol fed rabbits, an animal model of atherosclerosis, levels of F2-Isop's esterified to plasma lipids are markedly increased and are suppressed by the antioxidant, BHT. Studies are thus proposed to determine, using varying doses of vitamins C and E and beta-carotene, if levels of F2-Isop's esterified to plasma lipids in these animals predict and correlate with what occurs in the vascular wall, i.e. oxidation of lipids and extent of atherosclerosis. A role for the 12/15-lipoxygenase in the cellular oxidation of LDL has been suggested, although not proven. Another study is proposed to determine whether the oxidation of lipoproteins and the extent of atherosclerosis is reduced in Apo-E deficient mice, a mouse model of atherosclerosis, that have been mated with 12/15-lipoxygenase deficient mice and also in single 12/15 lipoxygenase deficient mice fed an atherogenic diet.

自由基与越来越多的人类健康有关 疾病。 最近我们发现了一系列类前列腺素F2 独立生产的化合物，称为 F2-异前列烷 (F2-Isop) 环氧合酶通过自由基催化的过氧化反应 花生四烯酸。 F2-Isop['s 原位酯化形成 磷脂并释放预制。 我们已经积累了相当可观的 有证据表明 F2-Isop 的测量代表了重要的 我们评估人类氧化应激状态的能力取得了进步。 提出了一项研究来增强我们评估内源性的能力 通过测量 F2-Isop 的尿代谢物来生产 F2Isop，8- 异-PGF2α。 为了实现这一目标，我们计划确定代谢命运 猴子体内 8-iso-PGF2alpha 的研究作为未来开发的基础 8-iso-PGF2α 尿代谢物的质谱分析。 抗氧化剂人体试验正在考虑的主要领域之一 使用维生素 C、维生素 E 和 β-胡萝卜素治疗可预防 动脉粥样硬化。 然而，这些药物的临床药理学 没有被定义。 我们发现，高脂血症患者， 血浆脂质中 P2-Isop 酯化水平升高。 因此，一项研究是 建议确定这些药物的剂量依赖性作用 高脂血症患者可单独或联合使用。 大量证据表明，低密度脂蛋白的氧化是一种 动脉粥样硬化形成中的关键事件，将 LDL 转化为可被 LDL 吸收的形式 巨噬细胞，导致泡沫细胞形成。 在用胆固醇喂养的兔子中， 动脉粥样硬化动物模型，F2​​-Isop 酯化水平 血浆脂质显着增加并被抗氧化剂抑制， BHT。 因此建议进行研究以确定使用不同剂量的 维生素 C 和 E 以及 β-胡萝卜素，如果 F2-Isop 的酯化水平达到 这些动物的血浆脂质预测并与发生的情况相关 血管壁，即脂质氧化和动脉粥样硬化程度。 12/15-脂氧合酶在 LDL 细胞氧化中的作用已被证实 建议，尽管尚未证实。 建议进行另一项研究以确定 脂蛋白的氧化与动脉粥样硬化的程度是否有关 Apo-E 缺陷小鼠（一种动脉粥样硬化小鼠模型）中的 已与 12/15-脂氧合酶缺陷型小鼠交配，并且在单 12/15 脂氧合酶缺陷小鼠喂食致动脉粥样硬化饮食。