权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

METABOLISM AND CARCINOGENICITY OF AFLATOXINS

黄曲霉毒素的代谢和致癌性

基本信息

批准号：
3249420
负责人：
GEORGE S BAILEY
金额：
$ 10.45万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1978
资助国家：
美国
起止时间：
1978-04-01 至 1989-03-31
项目状态：
已结题

项目摘要

The overall aim of this project is to precisely determine the carcinogenicities of 4 related aflatoxins (AFB1, AFL, AFM1, AFL-M1) and to understand their relative carcinogenic potencies in terms of: patterns of cellular metabolism; maximum quantities and types of DNA adducts formed; persistence of individual adducts; and the relative frequencies with which each adduct forms and persists on specific oncogene nucleotide sites implicated in cell transformation and tumor initiation. The 4 aflatoxins form a model analogue series for examinig fundamental structure-activity relationships in cancer initiation by bulky carcinogens. Trout are perhaps the only developed vertebrate model with sufficient sensitivity to test nanogram doses of rare aflatoxins, and of sufficient low cost that such studies (which involve 7200-animal tumor experiments) are reasonably supportable. To achieve this goal there are several Specific Aims: 1) We wish to precisely determine the relative carcinogencities of 4 aflatoxins, and separately, of their 4 dihalide activated derivatives, by direct trout embryo mciroinjection. We will also determine the embryo distribution and maximum covalent DNA binding indices (CBI) for each aflatoxin, and use a statistical model to examine the hypothesis that differences in CBI alone predict relative tumorigenicities among these aflatoxins or, separately, their dihalides. 2) We also examine the relationship between relative carcinogenicites among aflatoxins, and the exposure protocols (embryo vs. dietary) used to determine the relative carcinogencities. 3) Mechanism studies will examine the extent to which relative carcinogenicities reflect individual adduct structures, their persistence in vivo and in vitro, and the relative frequencies with which each aflatoxin adduct is formed at various guanyl sites in a cloned c-ras protooncogene including codon 12 guanines. Experiments will be conducted to compare site-specific rates of guanyl depurination among aflatoxin adducts, and to determine the relative potencies for transformation of NIH 3T3 cells among c-ras plasmids containing known levels of adducts, or apurinic sites, at each guanine including condon 12 sites. These studies should considerably improve our understanding of the biochemical and molecular mechanisms underlying differential carcinogenicities and mutagencities among related bulky carcinogens. They may also provide unique information on a fundamental question in carcinogenesis, namely whether c-ras activation is causative for tumor initiation.

这个项目的总体目标是准确地确定 4种相关黄曲霉毒素(AFB1、AFL、AFM1、 AFL-M1)，并了解它们的相对致癌能力在以下方面：细胞新陈代谢模式；最大数量和DNA加合物形成的类型；个体的持久性以及每个加合物的相对频率形成并持续存在于特定的癌基因核苷酸位点与细胞转化和肿瘤启动有关。四人组黄曲霉毒素构成检验基础的模范模拟系列大块致癌过程中的构效关系致癌物质。鲑鱼可能是唯一发育成熟的脊椎动物模型具有足够的灵敏度来测试纳克剂量的稀有黄曲霉毒素，而且成本足够低，这样的研究(即涉及7200个动物肿瘤实验)是合理的是可以支持的。为了实现这一目标，有几个具体目标： 1)我们希望准确确定以下物质的相对致癌性 4黄曲霉毒素，并分别激活其4个二卤化物中的衍生品，由直接鲑鱼胚胎微注射。我们还将确定胚胎分布和最大共价DNA 每个黄曲霉毒素的结合指数(CBI)，并使用统计模型检验假设仅在CBI中的差异预测这些黄曲霉毒素之间的相对致瘤性，另外，他们的二卤化物。2)我们还考察了黄曲霉毒素中相对致癌物质与暴露方案(胚胎与饮食)用于确定相对致癌性。3)机制研究将审查相对致癌性反映个体的程度加合物结构，它们在体内和体外的持久性，以及各黄曲霉毒素加合物形成的相对频率在克隆的c-ras原癌基因中的不同鸟苷酸位置，包括密码子12鸟嘌呤。将进行实验以比较黄曲霉毒素中鸟嘌呤脱嘌率的位点特异性加合物，并确定相对势能含c-ras基因的真核表达载体转化NIH 3T3细胞的研究已知水平的加合物，或无嘌呤位置，在每个鸟嘌呤包括密码子12位点。这些研究应该在很大程度上提高我们对生物化学和分子生物学的认识不同致癌性和致癌性差异的机制相关大块致癌物之间的致突变性。他们还可以中的一个基本问题提供独特的信息致癌作用，即c-ras激活是否与肿瘤的发生有关肿瘤的起源。