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PATHWAYS OF ACTIVATION AND DNA ADDUCTS OF CYCLOPENTA PAH

环五 PAH 的激活途径和 DNA 加合物

基本信息

批准号：
3191817
负责人：
Avram Gold
金额：
$ 14.82万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-07-15 至 1993-06-30
项目状态：
已结题

项目摘要

This proposal concerns the metabolism, biological activity and DNA adduct formation of a series of PAH which may be activated via epoxidation of a cyclopenta ring fused to the molecular periphery: cyclopenta(cd)pyrene, I benz(j)aceanthrylene, II; benz(l)aceanthrylene, III; naphtho (2,1,8-hij)acephenanthrylene, IV; and dibenzo(b, mno)acephenanthrylene, V. The long-term goals of this study are to gain insight into the effects of molecular geometry and peripheral functionalization (e.g. vicinal hydroxy groups of diolepoxides) on mutagenic and carcinogenic activity. Such information will ultimately be important in the rational selection of DNA lesions to serve as models is the elucidation of mechanisms linking DNA adducts to genetic effects. Of the PAH proposed for study, preliminary results on the metabolism and biological activity of I - III demonstrate that these compounds transform C3H10T1/2 cells, form DNA adducts and that the most potent activity results from II which can be activated either by a cyclopenta epoxide or a bay region diolepoxide. Compound I should be activated by cyclopenta ring epoxidation and III must be activated by multiple pathways. Short terms goals will be (1) synthesis of IV, V and determination of mutagenicity and cell transforming activity; (2) identification of ultimate active metabolities of I - III and/or IV, V (contingent on cell transforming activity); (3) synthesis of standards for identification of DNA adducts of I - III and/or IV, V,; (4) identification and quantitation of DNA adducts of C3H1OT1/2 cells treated with the tographic properties of adducts and suitably prepared standards by 32-p-postlabeling techniques or by HPLC, utilizing 3H-labeled PAH for treatment of C3H10T1/2 cells. Conclusions should be possible regarding the importance of the bay region diolepoxide metabolites in cell transformation and their activity relative to cyclopenta epoxides, as well as the generality of the regioselectivity of activated PAH metabolites for addition to the exocyclic amino group of guanosine and the relevance of this lesion to the transformation of C3H10T1/2 cells.

该提案涉及代谢、生物活性和一系列可能被激活的PAH的DNA加合物形成通过环氧化与分子稠合的环戊二烯并环，外围：环戊二烯并（cd）芘，I苯并（j）乙炔，II; 萘并（2，1，8-hij）乙酰菲，IV; 和二苯并（B，mno）乙酰菲，V.的长期目标，这项研究是为了深入了解分子几何形状和外围官能化（例如邻位羟基二醇环氧化物）的诱变和致癌活性。这些信息最终将是重要的理性选择DNA损伤作为模型是阐明将DNA加合物与遗传效应联系起来的机制在建议研究的多环芳烃中， I-III的代谢和生物活性表明，这些化合物转化C3 H10 T1/2细胞，形成DNA加合物，最有效的活性来自II，通过环戊二烯并环氧化物或海湾区域活化二羟环氧化合物化合物I应该是被环戊二烯环活化的环氧化和III必须通过多种途径活化。短术语的目标将是（1）综合IV，V和确定致突变性和细胞转化活性;（2）鉴定 I-III和/或IV、V的最终活性代谢（视情况而定）细胞转化活性）;（3）标准品的合成鉴定I-III和/或IV，V的DNA加合物;（4） C3 H1 OT 1/2 DNA加合物鉴定和定量用加合物的拓扑性质处理的细胞，通过32-p-后标记技术或HPLC制备标准品，利用~ 3 H标记的PAH处理C_3H_10T_1/2细胞。应该能够就下列问题的重要性得出结论：细胞转化中的海湾地区二乙醇环氧化物代谢物，它们相对于环戊环氧化物的活性，以及活化PAH代谢物的区域选择性的一般性用于加成到鸟苷的环外氨基上，该病变与C3 H10 T1/2细胞转化的相关性。