DIET, SMOKING & ALCOHOL INDUCED OXIDANT INJURY

摘要：本研究明确了氧化损伤在酒精摄入和病毒感染引起的肝损伤中的作用，并确定抗氧化维生素是否调节了这一作用。具体来说，我利用了一种最近被描述的方法来定量评估体内自由基的产生——测量异前列腺素——来解决自由基（FR）的产生发生在酒精诱导的肝损伤的明显模型中，并被抗氧化维生素摄入抑制的假设。我将这一体内生成FRs的标记物与一种已建立的体外氧化损伤测定法——共轭二烯的测定法进行了比较。此外，我探索了血栓素A2介导的血管收缩导致肝损伤加重的理论，虽然阿司匹林减少了酶促产生的血栓素A2代谢物，但异前列腺素的排泄没有改变。我们最近的研究表明，与年龄和性别匹配的健康对照组相比，通过尿8-epi PGF2形成测量，酒精性肝病和丙型肝炎肝硬化患者的氧化应激水平均有所增加。8-epi PGF2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。本研究探讨了抗氧化维生素对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的一个机制。其他研究者提出血栓素通过血栓素/ PGH2受体起作用，通过引起血管收缩促进乙醇喂养大鼠的肝损伤。我测量了同一组肝病患者在服用阿司匹林前后的11 -脱氢- TxB2（血栓素A2的尿代谢产物）水平。自由基在酶周转过程中产生，细胞色素P450异构体CYP2E1的诱导被认为是酒精消耗过程中FR产生的一个来源。同样，FRs也可以作为细胞刺激后酶活化的副产物产生。血小板和中性粒细胞的活化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外，8-epi PGF2也可以作为环加氧酶周转的次要产物形成。本研究提出了一种假设，即该途径对体内化合物的整体生物合成有重要贡献，表明在给药阿司匹林（一种环加氧酶抑制剂）后，尿8-epi PGF2的排泄或偶联二烯的形成没有改变。

Abstract: This study defined 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 A2 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 PGF2 formation when compared with age and gender matched healthy controls. The source of the increased 8-epi PGF2 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 PGF2 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 PGF2 excretion or conjugated diene formation following the administration of aspirin, a cyclooxygenase inhibitor, to patients with established liver disease.