SEQUELA OF WY-14, 643-INDUCED OXIDATIVE STRESS

过氧化物酶体增殖物是一组结构不同的 会导致分子的数量和大小都增加的化合物 过氧化物体，提高细胞增殖率并导致肝脏 啮齿动物的癌症。虽然致癌的机制不是 已知，已经提出了两个主要假设。一种观点认为氧化 应激是致癌过程中的关键事件，而 其他人认为，提高和持续的细胞复制是 对肿瘤的诱发负责。后者被认为是 是促进的主要机制，尽管，氧化的作用 启蒙过程中的压力是有争议的。然而，这两个假设 并不是相互排斥的。在令人兴奋的新实验中，我们展示了 至少一种碱基切除修复酶上调 通过长期给药WY-14,643，一种模型过氧化物酶 扩散者。这就引出了一个假设，即过氧化物酶 增殖剂诱导氧化DNA的形成增加 这些损伤的加合物和修复。此外，我们假设 氧化应激参与细胞的信号转导 增殖导致更高的突变、升级概率 和进步。我们将利用NTP研究中的冰冻组织 要调查以下问题：1)过氧化物体增殖物 诱导啮齿动物体内形成氧化和/或亚甲基DNA加合物 肝脏？2)DNA修复在过氧化物酶增殖物中起作用吗？ 诱导致癌？3)自由基的增加 与氧化剂一致的长期接触过氧化物酶增殖物 作为细胞增殖的信号机制？我们预测， 肝脏氧化性DNA损伤与 过氧化物酶体增殖物的致癌作用是由于 已研究的有限数量的DNA加合物及其诱导 修复DNA的能力。开发出最先进的设备和技术 在这个实验室里将让我们看到DNA的广泛光谱 加合物，多种DNA修复酶的活性，标记 氧化应激与细胞信号转导途径 扩散。我们希望找到一个很好的相关性 过氧化物酶体增殖物的肝癌致癌作用及其机制 利用有反应的物种(大鼠)和 无反应物种(仓鼠)。NTP研究的独特设计 将使我们能够使用来自WY-14,643的组织来检验我们的假设- 通过比较不同剂量和时间的暴露率和仓鼠 积分。这一新应用的优势在于 对旨在填补关键空白的特定假设进行评估 我们对这一重要的作用机制(S)的认识 但人们对这类化合物知之甚少。这项研究还将 对基于机械的风险有重要影响 评估。

Peroxisome proliferators are a group of structurally diverse compounds that cause an increase in both the number and size of peroxisomes, elevate rates of cell proliferation and cause liver cancer in rodents. Although the mechanism of carcinogenesis is not known, two main hypotheses have been proposed. One views oxidative stress as a critical event in the carcinogenic process, while the other contends that elevated and sustained cell replication is responsible for the induction of tumors. The latter is considered to be the main mechanism of promotion, although, the role of oxidative stress in initiation is controversial. However, these two hypotheses are not mutually exclusive. In exciting new experiments, we showed that at least one of the base excision repair enzymes is upregulated by chronic administration of WY-14,643, a model peroxisome proliferator. This led us to the hypothesis that peroxisome proliferators induce both increased formation of oxidative DNA adducts and repair of these lesions. Furthermore, we hypothesize that oxidative stress is involved in signaling pathways for cell proliferation leading to higher probabilities of mutation, promotion and progression. We will utilize frozen tissues from the NTP study to investigate following questions: 1) Do peroxisome proliferators induce the formation of oxidative and/or etheno DNA adducts in rodent liver? 2) Does DNA repair play a role in peroxisome proliferator- induced carcinogenesis? 3) Are increases in free radicals following chronic exposure to peroxisome proliferators consistent with oxidants as a signaling mechanism for cell proliferation? We predict that the poor correlation between hepatic oxidative DNA lesions and carcinogenic potency of peroxisome proliferators is due to the limited number of DNA adducts that has been studied and the induction of DNA repair. State-of-the-art equipment and techniques developed in this laboratory will allow us to look at a broad spectra of DNA adducts, the activity of multiple DNA repair enzymes, markers of oxidative stress, and a signal transduction pathway for cell proliferation. We expect to find a good correlation between hepatocarcinogenic potency of peroxisome proliferators and their ability to produce oxidants using a responsive species (rat) and a nonresponsive species (hamster). The unique design of the NTP study will allow us to examine our hypotheses using tissues from WY-14,643- exposed rates and hamsters by comparing different doses and time points. The strengths of this novel application lie in the evaluation of specific hypotheses designed to fill critical gaps in our knowledge regarding the mechanism(s) of action of this important but poorly understood class of compounds. This research also will have important implications for mechanistically based risk assessment.