EFFECTS OF DIETARY SELENIUM ON THE INITIATION OF DMBA

膳食硒对 DMBA 启动的影响

基本信息

批准号：
3187215
负责人：
JOHN A. MILNER
金额：
$ 12.72万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
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：
1988-07-01 至 1992-06-30
项目状态：
已结题

项目摘要

We have shown some forms of Se reduce DNA binding and formation of specific adducts when 7,12- dimethylbenz(a)anthracene (DMBA) is added to cultures of rat mammary epithelial and mouse embryo cells. Such results are consistent with data showing Se is able to inhibit the initiation phase of DMBA carcinogenesis. The proposed studies will determine if similar effects are observed in the intact rat given supplemental Se, what factors modify the response to Se and to correlate these adduct patterns with ultimate tumor formation. Studies using isolated mammary cells from rats fed identical diets will be used to establish a valid in vitro/ in vivo model and for evaluation of the mechanism by which selenium inhibits the initiation phase of carcinogenesis. A variety of in vivo and in vivo/ in vitro studies will evaluate the quantity and form of dietary Se and dose of DMBA on binding and adduct formation in mammary tissue. A post label 32p assay will be developed for the sensitive determination of DNA adducts. The decrease in anti- dihydrodiol adducts caused by Se appears to relate to reduced induction of enzyme(s). Additional studies will examine the effects of selenium upon the metabolism profiles of DMBA to help locate specific sites were Se may inhibit. Metabolites of DMBA and related compounds will be used to verify the site appearing most affected by Se. Sufficient rats will be fed the experimental diets and given DMBA to allow for comparison of specific changes in binding and adduct pattern during initiation upon the final tumor incidence and total tumor number. These studies will also correlate the influence of selective changes in DMBA metabolites and in the adducts that bind to DNA with ultimate mammary tumor development. These studies will likely have broad implications with various carcinogens requiring metabolic activation.

我们已经证明某些形式的 Se 会减少 DNA 结合并当 7,12- 时形成特定的加合物将二甲基苯并(a)蒽 (DMBA) 添加到大鼠培养物中乳腺上皮细胞和小鼠胚胎细胞。这样的结果是与显示 Se 能够抑制引发的数据一致 DMBA 致癌阶段。拟议的研究将确定在给定的完整大鼠中是否观察到类似的效果补充硒，哪些因素会改变对硒的反应以及将这些加合物模式与最终的肿瘤形成相关联。使用来自喂食相同饮食的大鼠的分离乳腺细胞进行的研究将用于建立有效的体外/体内模型并用于评估硒抑制的机制癌变的起始阶段。体内和体内的各种体内/体外研究将评估膳食 Se 和 DMBA 剂量对结合和加合物形成的影响乳腺组织。将开发标签后 32p 检测 DNA 加合物的灵敏测定。抗的减少由 Se 引起的二氢二醇加合物似乎与还原有关酶的诱导。额外的研究将检验硒对 DMBA 代谢谱的影响有助于定位被Se可能抑制的特定位点。 DMBA 代谢物和相关化合物将用于验证出现的站点受硒影响最大。将喂养足够的实验大鼠饮食并给予 DMBA 以允许比较特定的变化在最终启动过程中的结合和加合物模式肿瘤发生率和肿瘤总数。这些研究也将关联 DMBA 代谢物选择性变化的影响以及与最终乳腺 DNA 结合的加合物肿瘤的发展。这些研究可能会具有广泛的与需要代谢的各种致癌物的影响激活。