ANTIOXIDANT MODULATION OF FREE RADICAL GENERATION IN CIRRHOSIS

抗氧化剂调节肝硬化中自由基的产生

• 批准号: 6113294
• 负责人: EMMA MEAGHER
• 金额: $ 2.51万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6113294
• 关键词: alcoholic liver cirrhosis; antioxidants; aspirin; clinical research; free radical scavengers; free radicals; human subject; human therapy evaluation; liver circulation; liver cirrhosis; liver infection; nutrition related tag; oxidative stress; prostaglandin receptor; thromboxanes; vasoconstriction; virus diseases; vitamin therapy

This study defines the role oxidant injury plays in mediating hepatic injury caused by alcohol ingestion and viral infection, and to determine whether antioxidant vitamins modulate this effect. Specifically, I took advantage of a recently characterized approach to the quantitative assessment of free radical generation in vivo - measurement of isoprostanes - to address the hypothesis that free radical(FR) generation occurs in overt models of alcohol induced liver injury and is suppressed by antioxidant vitamin intake. I compared this marker of in vivo generation of FRs with an established ex vivo assay of oxidative injury - measurement of conjugated dienes. In addition, I explored the theory that vasoconstriction mediated by thromboxane A(2) results in exacerbation of hepatic injury and that while the enzymatically produced metabolite of thromboxane A2 is reduced by aspirin administration there is no alteration in isoprostane excretion. We have recently shown that patients with both alcohol induced liver disease and hepatitis C induced cirrhosis have increased levels of oxidative stress as measured by urinary 8-epi PGF(2a) formation when compared with age and gender matched healthy controls. The source of the increased 8-epi PGF(2a) biosynthesis is unclear. Alcoholics are traditionally thought to consume a diet deficient in antioxidant vitamins. This study addressed the effect of antioxidant vitamin administration on this marker of oxidative injury in patients with established cirrhosis. Vasoconstriction of blood vessels supplying the liver leading to intrahepatic hypoxia has been proposed as one mechanism involved in the pathogenesis of alcoholic liver disease. Other investigators have proposed that thromboxanes acting via the thromboxane/ PGH2 receptors, promote liver injury in the ethanol fed rats by causing vasoconstriction. I measured levels of 11 - dehydro - TxB2, the urinary metabolite of thromboxane A2 in the same group of patients with established liver disease both before and after dosing with aspirin. Free radicals are generated during enzyme turnover and the induction of the cytochrome P450 isoform, CYP2E1, has been implicated as a source of FR generation during alcohol consumption. Similarly, FRs may be generated as a byproduct of enzyme activation upon cellular stimulation. Activation of platelets and neutrophils is a feature of cirrhosis and both may result in FR generation. Additional to its generation by a free radical catalyzed process, 8-epi PGF(2a) may also be formed as a minor product of cyclooxygenase turnover. This study addresses the hypothesis that this pathway contributes trivially to overall biosynthesis of the compound in vivo by showing no alteration in urinary 8-epi PGF(2a) excretion or conjugated diene formation following the administration of aspirin, a cyclooxygenase inhibitor, to patients with established liver disease.

这项研究明确了氧化损伤在介导酒精摄入和病毒感染引起的肝损伤中所起的作用，并确定抗氧化维生素是否可以调节这种作用。 具体来说，我利用最近表征的体内自由基生成的定量评估方法（异前列烷的测量）来解决自由基（FR）生成发生在酒精引起的肝损伤的明显模型中并被抗氧化维生素摄入所抑制的假设。 我将这种体内生成 FR 的标记与已建立的氧化损伤离体测定（共轭二烯的测量）进行了比较。 此外，我还探讨了这样的理论：血栓素 A(2) 介导的血管收缩会导致肝损伤加剧，并且虽然服用阿司匹林会减少酶促产生的血栓素 A2 代谢物，但异前列腺素的排泄不会发生变化。 我们最近发现，与年龄和性别匹配的健康对照相比，通过尿液 8-epi PGF(2a) 形成测量，患有酒精诱发肝病和丙型肝炎诱发肝硬化的患者氧化应激水平增加。 8-epi PGF(2a) 生物合成增加的来源尚不清楚。传统上认为酗酒者的饮食缺乏抗氧化维生素。 本研究探讨了服用抗氧化维生素对已确诊肝硬化患者氧化损伤标志物的影响。供应肝脏的血管收缩导致肝内缺氧已被认为是酒精性肝病发病机制的一种机制。 其他研究人员提出，血栓素通过血栓素/PGH2 受体发挥作用，通过引起血管收缩，促进乙醇喂养大鼠的肝损伤。 我在服用阿司匹林之前和之后测量了同一组已确诊肝病患者的 11-脱氢-TxB2（血栓素 A2 的尿液代谢物）水平。自由基是在酶周转过程中产生的，并且细胞色素 P450 同种型 CYP2E1 的诱导被认为是饮酒过程中 FR 产生的来源。 类似地，FRs 可能作为细胞刺激后酶激活的副产物而产生。 血小板和中性粒细胞的激活是肝硬化的一个特征，两者都可能导致 FR 的产生。 除了通过自由基催化过程生成之外，8-epi PGF(2a) 也可能作为环氧合酶周转的次要产物而形成。 本研究提出了这样的假设：该途径对体内化合物的整体生物合成有微不足道的贡献，结果显示，在患有肝病的患者服用阿司匹林（一种环氧合酶抑制剂）后，尿液中 8-epi PGF(2a) 排泄或共轭二烯形成没有变化。