PATHWAYS OF ACTIVATION AND DNA ADDUCTS OF CYCLOPENTA PAH
PATHWAYS OF ACTIVATION AND DNA ADDUCTS OF CYCLOPENTA PAH
批准号:
3191816
负责人:
Avram Gold
金额:
$14.77万
依托单位国家:
美国
项目类别:
财政年份:
1988
资助国家:
美国
项目状态:
已结题
起止时间:
1988-07-15 至 1991-06-30
关键词:
DNA adduct benzanthracenes benzopyrenes bioassay carbopolycyclic compound chemical carcinogen chemical carcinogenesis chemical structure function chemical synthesis cyclopentane diol epoxides halobiphenyl /halotriphenyl compound high performance liquid chromatography laboratory rat liver metabolism microsomes mutagen testing nucleic acid chemical synthesis radiotracer tissue /cell culture tritium
中文摘要
该提案涉及新陈代谢、生物活性和
DNA加合物形成一系列可能被激活的PAH
通过与分子稠合的环戊环的环氧化
外围:环戊(cd)芘,I,苯并(j)苊,II;
苯并(l)苊,III;萘并(2,1,8-hij)苊菲,IV;
和二苯并(b,mno)苊菲,V.的长期目标
这项研究的目的是深入了解分子的影响
几何形状和外围功能化(例如邻羟基
二醇环氧化物基团)的致突变和致癌活性。
这些信息最终将在理性思考中发挥重要作用。
选择 DNA 损伤作为模型是为了阐明
将 DNA 加合物与遗传效应联系起来的机制。
拟议研究的 PAH 的初步结果
I - III 的代谢和生物活性表明
这些化合物转化 C3H10T1/2 细胞,形成 DNA 加合物
最有效的活性来自 II,可以是
由环戊环氧化物或湾区激活
二醇环氧化物。 化合物 I 应被环戊环活化
环氧化和 III 必须通过多种途径激活。 短
术语目标将是 (1) IV、V 的合成并确定
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(取决于
细胞转化活性); (3) 标准综合
I-III和/或IV、V的DNA加合物的鉴定; (4)
C3H1OT1/2 DNA 加合物的鉴定和定量
用加合物的拓扑特性处理的细胞,并适当地
通过 32-p-后标记技术或通过 HPLC 制备标准品,
利用 3 H 标记的 PAH 处理 C3H10T1/2 细胞。
关于其重要性的结论应该是可能的
湾区二烯环氧丙烷代谢物在细胞转化中的作用
它们相对于环戊环氧化物的活性,以及
活化 PAH 代谢物区域选择性的一般性
用于添加鸟苷的环外氨基和
该损伤与 C3H10T1/2 细胞转化的相关性。
英文摘要
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.
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