METABOLIC ACTIVATION OF MONOMETHYLBENZ ANTHRACENES

单甲基苯蒽的代谢激活

• 批准号: 3168560
• 负责人: SHEN K. YANG
• 金额: $ 7.28万
• 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/3168560
• 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; tritium; 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）蒽 冷凝物、烟道气和屋顶焦油提取物， 环境对人类的危害。在十二个异构MBA中，7-MBA是最 最活跃的皮肤致癌物，6-，8-，12-MBA活性较低，其他MBA 皮下注射时无活性或轻微活性， 画在老鼠的皮肤上 不同的分子基础 这12位MBA的具体情况目前尚不清楚。 自从MBA毕业以来 需要代谢才能发挥其致癌性，可能的差异 在它们的代谢途径中， 将研究致癌效力。 拟议的研究包括： (1)未标记和氚标记MBA的合成;（2）详细 每种MBA在大鼠中的区域选择性和立体选择性代谢研究 体外肝微粒体和体内小鼠皮肤;（3）鉴定 通过高效液相色谱法从每个MBA酶促形成的代谢产物 色谱法、紫外和荧光分光光度法、质量和 核磁共振光谱法和旋光光谱法;（4） 细胞色素P-450的区域选择性和立体选择性研究 大鼠肝微粒体制备物的同工酶和环氧化物水解酶 通过分析环氧化物和二氢二醇， 通过使用分子氧-18和氧-18水以及通过 手性固定相高效液相色谱;（5） 通过酶和/或化学方法大规模制备MBA代谢物 方法：（6）MBA相对致突变活性测定， 鼠伤寒沙门氏菌试验菌株TA 100的代谢产物;（7）DNA MBA在小鼠皮肤中的体内结合活性;和（8）肿瘤起始 MBA及其代谢产物对小鼠皮肤的活性。 这些研究 将提供结构-活性关系的详细了解 的12个MBA及其相对致癌的分子基础， 效力