PATHWAYS OF ACTIVATION AND DNA ADDUCTS OF CYCLOPENTA PAH

这项建议涉及到新陈代谢、生物活性和 一系列可被激活的多环芳烃DNA加合物的形成 通过与分子融合的环戊环的环氧化反应 外围：环戊二烯(CD)、苯并苯(J)、乙基苯(II)； 苯并(L)苯并菲，III；萘(2，1，8-hij)乙酰菲，IV； 和二苯并(b，MnO)乙基菲，V. 这项研究是为了深入了解分子的影响 几何构型和外周官能化(例如邻羟基 对诱变和致癌活性的影响。 这些信息最终将在理性的 选择DNA损伤作为模型是对 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的代谢和生物活性证明 这些化合物转化C3H10T1/2细胞，形成DNA加合物 而最有效的活性来自II，它可以是 由环戊环氧化物或湾区激活 二环氧丙烷。化合物I应被环戊环激活 环氧化和III必须由多个途径激活。短的 术语目标将是(1)合成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)标准的合成 I-III和/或IV、V的DNA加合物鉴定；(4) C3H1OT1/2的DNA加合物的鉴定和定量 用加合物的图像学性质处理细胞并适当地 通过32P后标记技术或通过高效液相色谱制备标准品， ~3H标记PAH对C3H10T1/2细胞的作用 应该能够得出关于以下方面的结论 湾区二环氧化物代谢产物在细胞转化中的作用 它们相对于环戊烷环氧化物的活性，以及 活性多环芳烃代谢物区域选择性的一般性 用于添加鸟苷的外环氨基和 此病变与C3H10T1/2细胞转化的相关性。

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.