INFLUENCE OF ETHANOL ON CARCINOGEN ACTIVATION

本提案中概述的研究将研究发生在 乙醇和化学致癌物的代谢活化之间的关系。 分离的灌注肝脏和肝细胞将用于这些实验 因为致癌物的活化、结合和结合， 大分子可以在接近生理学的条件下同时进行研究。 条件 这项研究将针对三个主要目标。 第一章 慢性乙醇给药对肝细胞凋亡途径的影响 完整细胞中的混合功能氧化和结合将是 测定 中间代谢改变的影响与 乙醇喂养的辅因子的生物合成所需的两个 还将对过程进行评估。 2)急性添加的影响 将研究乙醇对致癌物活化的影响。 直接影响 乙醇对酶的影响将与以下因素引起的间接影响不同： 乙醇的代谢以及随后与以下途径的相互作用 辅因子生物合成 3)致癌物暴露对途径的影响 混合功能氧化，共轭，乙醇代谢和相关 还将评估代谢过程。 这些研究将利用 模型致癌物（例如，苯并（a）芘和二甲基亚硝胺）和 各种混合功能氧化酶的非致癌底物， 共轭途径 致癌物与大分子结合的变化 将与酶活性的变化， 细胞内中间产物，以及通过 表面荧光 以这种方式，致癌物的限速步骤 将建立完整细胞中的代谢。 的风险增加 酒精重度消费者的癌症已经被认为是重要的 健康问题。 此外，已经完成的研究表明， 急性和慢性暴露于乙醇之间发生的相互作用 以及参与的混合功能氧化和结合的速率 致癌物质的代谢 拟议的研究将侧重于界定 乙醇可能增加癌症风险的分子机制， 化学致癌物

The research outlined in this proposal will examine interactions occurring between ethanol and the metabolic activation of chemical carcinogens. Isolated perfused livers and hepatocytes will be used for these experiments because the activation, conjugation and binding of carcinogens to cellular macromolecules can be studied simultaneously under near physiological conditions. This research will be directed at three major objectives. 1) The influence of chronic ethanol administration on pathways of mixed-function oxidation and conjugation in intact cells will be determined. The effects of altered intermediary metabolism associated with ethanol feeding on the biosynthesis of cofactors required for both processes will also be evaluated. 2) The influence of the acute addition of ethanol on carcinogen activation will be studied. Direct effects on ethanol on enzymes will be differentiated from indirect effects caused by the metabolism of ethanol and subsequent interactions with pathways of cofactor biosynthesis. 3) The effects of carcinogen exposure on pathways of mixed-function oxidation, conjugation, ehtanol metabolism and related metabolic processes will also be assessed. These studies will utilize model carcinogens (e.g., benzo(a)pyrene and dimethylnitrosamine) and non-carcinogenic substrates for the various mixed-function oxidase and conjugation pathways. Changes in binding of carcinogens to macromolecules will be compared to changes in enzyme activities, altered concentrations of intracellular intermediates, and local changes in metabolism detected by surface fluorescence. In this manner, rate-limiting steps for carcinogen metabolism in intact cells will be established. An increased risk of cancer in heavy consumers of ethanol has been recognized as significant health problem. Moreover, studies already completed have demonstrated interactions occurring between both acute and chronic exposure to ethanol and rates of mixed-function oxidation and conjugation which are involved in the metabolism of carcinogens. The proposed studies will focus on defining molecular mechanisms by which ethanol may increase the risk of cancer from chemical carcinogens.