BIOCHEMICAL TOXICITY OF AGENTS INCREASING REACTIVE 02

在该更新申请中，提出研究以阐明 某些致癌性的毒理学机制 过氧化物酶体增殖剂（PPA）。 占优势的亚兽 有大量证据支持的机制是 这些药物会增加H2 O2的细胞水平， 大分子损伤和细胞改变。 前一 在此期间，我们无法获得直接确认 序列，但提出了进一步的实验来检查 以严谨的方式进行假设。 前一项调查结果 研究还引导我们考虑其他机制， 独立于氧化损伤或与氧化损伤一起起作用。 本研究的具体目标如下：（1） 确定两个遗传定义的小鼠组和一个PPA最 可能显示PPA诱导的肿瘤发生的差异，假设 H2 O2假设是正确的，并描述了剂量反应 PPA对两组肿瘤发生的影响;（2） PPA对肝细胞氧化损伤的研究 （3）研究PPA诱导的肝细胞凋亡 增殖作为PPA中的重要机制事件 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.