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: 6325859
• 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: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6325859
• 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疾病有关， 疾病 最近，我们发现了一系列前列腺素F2样 称为F2-异前列烷（F2-Isop）的化合物， 环氧合酶的自由基催化过氧化反应， 花生四烯酸 F2-异丙基酯原位形成， 磷脂和释放的预成型。 我们已经积累了大量的 有证据表明，F2-Isop的测量代表了一个重要的 我们在评估人类氧化应激状态的能力方面取得了进展。 一项研究提出，以提高我们的能力，评估内源性 通过测量F2-Isop的尿代谢物，8- iso-PGF 2 α。 为了实现这一目标，我们计划确定 8-iso-PGF 2 α在猴子中的表达作为未来开发的基础， 8-iso-PGF 2 α尿代谢物的质谱分析。 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 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， 与血浆脂质酯化的P2-Isop水平升高。 因此，研究 建议建立这些药物的剂量依赖性效应， 在高脂血症患者中单独和联合使用。 大量的证据表明，LDL的氧化是一种 动脉粥样硬化形成中的关键事件，将LDL转化为被 巨噬细胞，导致泡沫细胞形成。 在胆固醇喂养的兔子中， 动脉粥样硬化的动物模型中，酯化至 血浆脂质显著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 这些动物的血浆脂质预测并与 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LDL细胞氧化中的作用已经被证实。 建议，虽然没有证明。 另一项研究建议确定 脂蛋白氧化和动脉粥样硬化程度是否 在Apo-E缺陷小鼠（动脉粥样硬化的小鼠模型）中减少， 与12/15-脂氧合酶缺陷小鼠交配， 12/15脂肪氧合酶缺陷小鼠喂食致动脉粥样硬化饮食。