METABOLIC ACTIVATION OF MONOMETHYLBENZ ANTHRACENES

单甲基苯蒽的代谢激活

• 批准号: 3168552
• 负责人: SHEN K. YANG
• 金额: $ 8.29万
• 依托单位: U.S.UNIFORMED SERVICES UNIV HLTH SCIS
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-08-01 至 1990-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3168552
• 关键词: benzanthracenes; benzopyrenes; chemical carcinogen; chemical carcinogenesis; environment related neoplasm /cancer; fluorescence spectrometry; high performance liquid chromatography; mass spectrometry; methylcholanthrene; mutagen testing; nuclear magnetic resonance spectroscopy; polarimetry; radiotracer; skin neoplasms; toxicant screening; toxin metabolism; ultraviolet spectrometry

Methylbenz(a)anthracenes (MBAs) have been found in cigarette smoke condensates, stack gas and roofing tar extracts and are potentially environmental hazards to man. Among the twelve isomeric MBAs, 7-MBA is the most active skin carcinogen, 6-, 8-, 12-MBA are less active, and other MBAs are either inactive or slightly active when injected subcutaneously or painted on the skin of rats or mice. The molecular basis for the different carcingenicities of the twelve MBAs is currently unknown. Since MBAs require metabolism to exert their carcinogenicity, the possible differences in their metabolic pathways which may account for their relative carcinogenic potencies will be investigated. The proposed studies are: (1) synthesis of unlabeled and tritium-labeled MBAs; (2) detailed regioselective and stereoselective metabolic studies of each MBA in rat liver microsomes in vitro and in mouse skin in vivo; (3) identification of metabolites formed enzymatically from each MBA by high-performance liquid chromatography, ultraviolet and fluorescence spectrophotometry, mass and nuclear magnetic resonance spectroscopy, and spectropolarimetry; (4) studies on the regioselectivity and stereoselectivity of cytochrome P-450 isozymes and epoxide hydrolase of rat liver microsomal preparations in vitro and in mouse skin in vivo by analyzing the epoxide and dihydrodiol metabolites formed by using molecular oxygen-18 and oxygen-18 water and by chiral stationary phase high-performance liquid chromatography; (5) large-scale preparations of MBA metabolites by enzymic and/or chemical methods; (6) determination of relative mutagenic activities of MBA and metabolites with Salmonella typhimurium tester strain TA100; (7) DNA binding activities of MBAs in mouse skin in vivo; and (8) tumor-initiating activities of the MBAs and their metabolites on mouse skin. These studies will provide detailed understanding of the structure-activity relationships of the twelve MBAs and the molecular basis of their relative carcinogenic potencies.

在香烟烟雾中发现了甲基苯并(A)菲(MBAs)。 凝析油、烟道气和屋面焦油提取物，可能 对人类的环境危害。在12名异质MBA中，7-MBA是 最活跃的皮肤致癌物质，6-，8-，12-MBA活性较低，其他MBA 在皮下注射时不活跃或轻微活跃，或者 画在老鼠或老鼠的皮肤上。不同基因的分子基础 目前尚不清楚这12名MBA学生的具体情况。自从MBA毕业生 需要新陈代谢才能发挥其致癌作用，可能存在的差异 在他们的代谢途径中，这可能解释了他们的近亲 致癌能力将被调查。建议的研究包括： (1)未标记和氚标记的MBAs的合成；(2)详细 每种MBA在大鼠体内的区域选择性和立体选择性代谢研究 体外和体内小鼠皮肤中的肝微粒体；(3)鉴定 高效液体从每个MBA中酶解生成代谢物 层析、紫外和荧光分光光度、质量和 核磁共振波谱和光谱偏振法；(4) 细胞色素P-450的区域选择性和立体选择性研究 大鼠肝微粒体制剂的同工酶和环氧化物水解酶 环氧化物和二氢二醇在体外和体内小鼠皮肤的分析 利用分子氧-18和氧-18水形成的代谢物 手性固定相高效液相色谱法；(5) 酶和/或化学法大规模制备MBA代谢物 方法：(6)MBA相对致突变活性的测定； 鼠伤寒沙门氏菌测试菌株TA100的代谢产物；(7)DNA MBAs在小鼠皮肤中的体内结合活性；(8)致瘤作用 MBA及其代谢物对小鼠皮肤的作用。这些研究 将提供对结构-活动关系的详细理解 12名MBA及其相对致癌的分子基础 效力。