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: 6240387
• 负责人: L Jackson Roberts, II
• 金额: $ 25.27万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6240387
• 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.

自由基被认为与越来越多的人类 疾病。最近我们发现了一系列前列腺素F2样蛋白 独立生产的化合物，称为F2-异前列腺素(F2-Isop) 自由基催化过氧化对环氧合酶活性的影响 花生四烯酸。F2-异硫磷[‘S]原位酯化生成 磷脂和释放的预制体。我们积累了相当多的 有证据表明，F2-Isop的测量代表着一个重要的 我们评估人类氧化应激状态的能力取得了进展。 一项研究建议增强我们评估内源性的能力 通过测定F2-Isop的尿代谢物8-Isop来产生F2Isop ISO-PGF2α。为了这个目标，我们计划决定代谢的命运 8-iso-PGF_(2α)在猴体内的表达，为今后的研究奠定基础 尿液中8-iso-PGF2pha代谢物的质谱分析。 抗氧化剂人体试验的主要考虑领域之一 维生素C、维生素E和β-胡萝卜素的治疗是预防的 动脉粥样硬化。然而，这些药物的临床药理学已经 未定义。我们发现，高脂血症患者有 P2-Isop酯化为血脂的水平升高。因此，一项研究是 建议建立这些药物给出的剂量依赖效应 高脂血症患者单用和联合用药。 大量证据表明，低密度脂蛋白的氧化是一种 动脉粥样硬化发生中的关键事件，它将低密度脂蛋白转化为可被 巨噬细胞，导致泡沫细胞的形成。在喂胆固醇的兔子身上， 动脉粥样硬化动物模型中F2-Isop的酯化水平 血浆中的血脂显著升高，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 这些动物中的血浆脂类预测并与发生在 血管壁，即脂质的氧化和动脉粥样硬化的程度。 12/15-脂氧合酶在细胞氧化低密度脂蛋白中的作用 虽然还没有得到证实，但建议这样做。另一项研究是为了确定 脂蛋白的氧化与动脉粥样硬化的程度 在载脂蛋白E缺陷小鼠(动脉粥样硬化的小鼠模型)中， 已经与12/15-脂氧合酶缺陷小鼠交配，也在 15只脂肪氧合酶缺陷小鼠中有12只喂食致动脉粥样硬化的食物。