P450 MEDIATED LUNG TOXICITY

描述(改编自《调查者摘要》)：非致癌性 肺部疾病是美国的第三大死因，是 致残率和致残率的主要因素。肺癌是最主要的 癌症相关死亡的原因。尽管吸烟是一种主要的 这些疾病的病因，工作场所接触化学物质 在环境中的作用可能也很重要。大量的研究在 实验动物已经证明了肺作为靶子的重要性。 吸入和摄入的化学物质。因为对啮齿动物的研究 在物种和区域敏感性方面表现出高度的变异性 肺对这些化学物质的影响，在啮齿动物身上进行的研究对 估计接触人类的风险是有问题的。没有 对确定肺的关键因素的理解 对啮齿动物的毒性适用于解剖、细胞和 新陈代谢完全不同的人类肺。在可能影响到的因素中 肺对有毒化学物质的敏感性是细胞 关键代谢酶的分布及其催化活性 (细胞色素P450单加氧酶)生物激活惰性化学物质以 反应性的肺部有毒代谢物。这些研究检验了这一假设 一些由P450代谢激活的啮齿动物肺部毒物也会产生 人肺局灶性损伤。将检验三个假说：1)恒河猴 猕猴在解剖学和细胞上与人类相似，是一种 人体评价化学性肺损伤的合适替代物 毒性，2)单加氧酶在人体内的细胞分布 灵长类动物的肺高度集中，使这些细胞特别容易患上 3)肺组织P450‘S的催化活性。 猴子和人类很相似。三种啮齿动物肺的毒性 有毒物质，萘(NA)、1-硝基(NN)和4-异丙醇(IPO) 将在体外对恒河猴的肺、人类的肺和 敏感的啮齿动物模型(阳性对照)和在猴体内。这个 P450同工酶在细胞内的分布 啮齿动物的肺部毒物(细胞色素P450 2B、细胞色素P450 E、细胞色素P450 F、细胞色素P4B)将在 猴子和人的肺。重组P450(啮齿动物， 猴子和人类)将用NA、NN和IPO进行评估。这项工作应该是 使您更好地了解 啮齿动物、猴子和人类肺部对以下化学物质的生物反应 通过细胞色素P450单加氧酶系统进行代谢激活。

DESCRIPTION (Adapted from the Investigator's Abstract): Nononcogenic pulmonary diseases are the third leading cause of death in the US and are a major factor in morbidity and disability. Pulmonary cancer is the leading cause of cancer-related deaths. Although cigarette smoking is a major etiologic factor in these diseases, exposure to chemicals in the workplace and in the environment may be important as well. Numerous studies in laboratory animals have demonstrated the importance of the lung as a target for both inhaled and ingested chemicals. Because the studies in rodents have shown high variability in species and regional sensitivity within the lung to these chemicals, the applicability of studies in rodents for estimating the risks of exposure to humans is questionable. There is no understanding of how the factors thought to be critical for determining lung toxicity in rodents applies to the anatomically, cellularly, and metabolically distinct human lung. Among the factors likely to influence the susceptibility of the lung to toxic chemicals are the cellular distribution and catalytic activities of the key metabolic enzymes (cytochrome P450 monooxygenases) which bioactivate inert chemicals to reactive, lung toxic metabolites. These studies test the postulate that some rodent lung toxicants metabolically activated by P450 also produce focal injury in human lung. Three hypotheses will be tested: 1) the Rhesus macaque, which is anatomically and cellularly similar to humans, is an appropriate surrogate for humans in evaluating chemical-induced lung toxicity, 2) the cellular distribution of monooxygenases in human and primate lungs is highly focal making those cells particularly susceptible to cytotoxicants, and 3) the catalytic activities of pulmonary P450's in monkeys are similar to the human. The toxicity of three rodent lung toxicants, naphthalene (NA), 1-nitronaphthalene (NN) and 4-ipomeanol (IPO) will be evaluated in vitro in lungs of Rhesus monkeys, humans, and in sensitive rodent models (positive controls) and in vivo in monkeys. The cellular distribution of P450 isozymes responsible for the bioactivation of lung toxicants in rodents (CYP2B, CYP2E, CYP2F, CYP4B) will be defined in monkey and human lung. The catalytic activity of recombinant P450s (rodent, monkey and human) will be assessed with NA, NN and IPO. This work should provide a better understanding of the similarities and differences in the biologic response of lungs of rodents, monkeys, and humans to chemicals that undergo metabolic activation by the cytochrome P450 monooxygenase system.