BIOALKYLATION IN CHEMICAL CARCINOGENESIS

化学致癌作用中的生物烷基化

• 批准号: 3189117
• 负责人: James W Flesher
• 金额: $ 0.69万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-30 至 1991-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3189117
• 关键词: S adenosylmethionine; alkyl group; alkylation; anthracenes; benzanthracenes; benzopyrenes; carbopolycyclic compound; carcinogen testing; carcinosarcoma; chemical carcinogenesis; chemical structure function; cytoplasm; laboratory rat; macromolecule; methylation; oxidation; pyrenes; tissue /cell culture

The objectives of this biochemical research are to explore the role and regulation of bioalkylation in the activation of PAHs in chemical carcinogenesis. The bioalkylation substitution reaction of PAHs, consists of a biochemical reaction between certain unsubstituted PAHs and S-adenosyl-L-methionine (SAM) that is catalyzed by cytosolic enzymes. The introduction of the alkyl group takes place in the reactive meso-anthracenic positions or L- region. The rate and extent of the bioalkylation reaction of anthracene, benz(a)anthrcene, benzo(a)pyrene, anthanthrene and pyrene will be measured in cytosol preparations of rat liver, lung and subcutaneous tissue. Although some evidence for bioalkylation of PAHs in vivo has already been obtained, it is obviously desirable to quantitate both the rate and extent of this new biochemical reaction with SAM and without added SAM for comparison with in vitro studies. In contrast to most studies in this field this alternative pathway of activation by soluble enzymes does not involve microsomal reactions but is entirely concerned with the biochemical reactions that occur in cytosol preparations that are essentially free of microsomes. An intimately associated biological oxidation of the hydrocarbon also occurs in cytosol preparations and studies that are designed to determine the mechanism of the oxidation will also be undertaken in collaboration with Dr. Lauren Tolbert. The biosynthetic products of these cytosolic reactions will be identified by HPLC and GC/MS in most cases by comparison with authentic reference compounds. Carcinogenic activity will be determined in rats by subcutaneous injection of the PAH with and without other compounds that may enhance or inhibit carcinogenic activity. The isolation and characterization of specific end products of reaction of the cytosolic metabolites and model ultimate metabolites with macromolecules in vivo will be explored.

这项生物化学研究的目的是探索 生物烷基化在多环芳烃活化中的作用和调控 化学致癌作用 生物烷基化取代反应 多环芳烃，由某些生物化学反应， 未取代的多环芳烃和S-腺苷-L-蛋氨酸（SAM）， 由胞质酶催化。 烷基的引入 基团发生在反应性内消旋蒽位置或L- 地区 蒽的生物烷基化反应的速率和程度， 苯并（a）蒽、苯并（a）芘、蒽嵌蒽和芘将 在大鼠肝、肺和 皮下组织 虽然一些证据表明，生物烷基化的 多环芳烃在体内已经得到了很好的研究， 来量化这种新的生化反应的速度和程度 与添加SAM和不添加SAM的反应进行比较， 体外研究。 与该领域的大多数研究相比， 可溶性酶的替代活化途径不 涉及微粒体反应，但完全与 在细胞质制备物中发生的生化反应， 基本上没有微粒体。 一个密切相关的 碳氢化合物的生物氧化也发生在胞质溶胶中 准备和研究旨在确定 氧化的机制也将进行， 与Lauren Tolbert博士合作。 生物合成产品 将通过HPLC鉴定这些胞质反应， 大多数情况下，通过与真实参比品进行比较进行GC/MS分析 化合物. 将通过以下方法测定大鼠的致癌活性： 皮下注射PAH，伴或不伴其他 可能增强或抑制致癌活性的化合物。 特异性终产物的分离和表征 胞质代谢物和模型终产物的反应 将探索体内具有大分子的代谢物。