32P LABELING TEST FOR NUCLEIC ACID DAMAGE BY CARCINOGENS

DNA加合物，可由外源和内源机制形成， 在肿瘤的发生和进展中发挥关键的机制作用 肿瘤过程。导致加合物形成的内源性化学物质可能 由于正常新陈代谢、活性氧的作用而产生 物种和接触致癌物(引发剂和促进剂)。因此， 内源性DNA加合物：与生活方式因素有机械联系。 有人建议开发营养和药理技术来 在体内调节内源性DNA加合物的形成，基于 关于调节剂作用机制的现有知识。一位少校 该项目的重点将是研究大块头的营养调节 组织中出现的氧化性DNA损伤(称为III型化合物) 正常出生时或出生后不久大鼠的DNA。其微量营养素含量 孕妇在怀孕期间和产后早期的饮食将 系统地改变，以便识别可能的营养 防止或加剧出生后DNA氧化损伤的因素。 其他实验将确定这些DNA加合物是否 与围产期大气含氧量的机械联系以及是否 它们的形成因谷胱甘肽(抗氧化剂)的耗尽而加剧。 使用促氧化致癌物质，靶器官依赖的形成和 氧化DNA损伤的持久性将在成年大鼠中进行调查 以进一步阐明两者之间可能的机制关系 这些DNA改变和癌症的发生。正相关关系将会 强烈支持出生后DNA氧化损伤是因果关系的观点 与晚年的肿瘤有关。这些实验还将表明 巨大的氧化性DNA损伤是否代表了一种更有效的 氧化应激相关的DNA损伤比8-氧脱氧鸟苷。第II类 I-化合物代表了一类庞大的内源性组织DNA修饰 它们与Il-型化合物不同。后者中的一些是 与癌症的发生成反比，因此内源性 DNA修饰被认为在正常情况下发挥作用 细胞。建议对这些化合物的化学结构进行表征 第I类和第III类--化合物，有足够的 来自体外和体内来源的量，按液体计算 层析/电喷雾串联质谱仪。进一步的研究将 探索胆固醇生物合成与类型之间的可能关系 I-I类化合物及药物调节剂对内源DNA的影响 加合物。 这个项目将增进我们对化学物质的作用机理的了解。 致癌，并希望最终将导致癌症预防 人类的策略。

DNA adducts, which may be formed by exogenous and endogenous mechanisms, play key mechanistic roles in carcinogenesis and the progression of the neoplastic process. Endogenous chemicals leading to adduct formation may arise as a consequence of normal metabolism, action of reactive oxygen species, and exposure to carcinogens (initiators and promoters). Thus, endogenous DNA adducts: are mechanistically linked to lifestyle factors. It is proposed to develop nutritional and pharmacological techniques to modulate the formation of endogenous DNA adducts in vivo, based on existing knowledge of the mechanisms of action of the modulators. A major focus of the project will be studies of nutritional modulation of bulky oxidative DNA lesions (termed type II I-compounds), which arise in tissue DNA of rats at or shortly after normal birth. The micronutrient content of the maternal diet during pregnancy and the early post-delivery period will be systematically varied in order to recognize possible nutritional factors preventing or exacerbating postnatal oxidative DNA lesions. Additional experiments will determine whether these DNA adducts are mechanistically linked to perinatal atmospheric oxygen content and whether their formation is intensified by glutathione (antioxidant) depletion. Using pro-oxidant carcinogens, the target organ-dependent formation and persistence of oxidative DNA lesions will be investigated in adult rats in order to further elucidate the possible mechanistic relationship between these DNA alterations and carcinogenesis. A positive correlation would strongly support the idea that postnatal oxidative DNA damage is causally linked to neoplasia later in life. These experiments will also show whether bulky oxidative DNA lesions represent a more valid biomarker of oxidative stress-associated DNA damage than 8-oxodeoxyguanosine. Type II I-compounds represent a class of bulky endogenous tissue DNA modifications which are distinct from type Il-compounds. Some of the latter are associated inversely with carcinogenesis, and therefore such endogenous DNA modifications are postulated to play a functional role in normal cells. It is proposed to characterize the chemical structures of those type I and type III-compounds, which are available in sufficient quantities from in vitro and in vivo sources, by liquid chromatography/electrospray tandem mass spectrometry. Further studies will explore possible relationships between cholesterol biosynthesis and type I I-compounds and effects of pharmacological modulators on endogenous DNA adducts. This project will enhance our knowledge of mechanisms of chemical carcinogenesis and, it is hoped, will eventually lead to cancer preventive strategies in humans.