BIOCHEMICAL TOXICITY OF AGENTS INCREASING REACTIVE 02

在这一续订申请中，建议进行研究以阐明 某些化合物的致癌性毒理学机制(S) 过氧化物酶体增殖剂(PPA)。占主导地位的低体温 机制，有大量的支持证据，是 这些制剂会增加细胞内的过氧化氢水平，从而导致 大分子损伤和细胞改变。在上一次 在授权期内，我们无法获得对此的直接确认 序列，但建议进行进一步的实验来检验 以严格的方式提出假设。前面的调查结果 研究还引导我们考虑其他机制，这可能 在不受氧化损伤的情况下运行或与氧化损伤一起运行。 本课题的具体研究目标如下：(1) 确定两个基因定义的小鼠群体和PPA Most 可能在PPA诱导的肿瘤发生中表现出差异，假设 双氧水假说是正确的，并描绘了剂量-反应 PPA对两组肿瘤发生的影响； PPA对肝细胞氧化损伤的研究 大分子；(3)研究PPA诱导的肝细胞 扩散作为PPA中的一个机械上的重要事件 致癌性。

In this renewal application, research is proposed to elucidate the toxicologic mechanism(s) for the liver carcinogenicity of certain peroxisome-proliferating agents (PPA). The dominant hypotherical mechanism, for which there is substantial supporting evidence, is that these agents increase cellular levels of H2O2 leading to macromolecular damage and cellular alteration. During the previous grant period, we were unable to obtain direct confirmation for this sequence, but further experiments are proposed to examine the hypothesis in a rigorous manner. Findings in the preceding research also lead us to consider additional mechanisms, which may operate independent of oxidative damage or in conjunction with it. The specific aims for the contimued research are as follows: (1) Identify two genetically-defined groups of mice and a PPA most likely to show differences in PPA-induced tumorigenesis, assuming the H2O2 hypothesis to be true and delineate the dose-response effects of that PPA on tumorigenesis in those two groups; (2) Investigate PPA-induced oxidative damage on liver cell macromolecules and; (3) Investigate PPA-induced liver cell proliferation as a mechanistically important event in PPA carcinogenicity.