P450 MEDIATED LUNG TOXICITY

描述（改编自研究者摘要）：非致癌性 肺部疾病是美国第三大死亡原因， 发病率和残疾的主要因素。 肺癌是导致 癌症相关死亡的原因。 虽然吸烟是一个主要的 这些疾病的病因，工作场所的化学品暴露 和环境中可能也很重要。 的大量研究 实验室动物已经证明了肺作为靶点的重要性 吸入和摄入的化学物质。 因为在啮齿类动物中的研究 已显示出物种的高度变异性和区域敏感性， 肺对这些化学品，在啮齿动物的研究适用性， 估计人类接触的风险是值得怀疑的。 没有 了解被认为是决定肺功能的关键因素 啮齿类动物的毒性适用于解剖学、细胞学和 与人类肺部代谢不同 在可能影响 肺对有毒化学物质的敏感性是细胞的 关键代谢酶的分布和催化活性 （细胞色素P450单加氧酶），其生物活化惰性化学物质， 反应性肺毒性代谢物。 这些研究验证了一个假设， 一些由P450代谢活化的啮齿类动物肺毒物也产生 人肺局灶性损伤。 三个假设将被测试：1）恒河猴 猕猴在解剖学和细胞学上与人类相似， 评价化学品诱导肺损伤的适当人体替代物 毒性，2）单加氧酶在人体内的细胞分布， 灵长类动物的肺是高度集中的，使得这些细胞特别容易受到 细胞毒素，和3）肺P450的催化活性， 猴子与人类相似。 三种啮齿动物肺的毒性 有毒物质，萘（NA），1-硝基萘（NN）和4-异戊烯醇（IPO） 将在恒河猴、人和小鼠的肺中进行体外评价。 敏感啮齿动物模型（阳性对照）和猴体内。 的 细胞分布的P450同工酶负责的生物活化 啮齿类动物中的肺毒物（CYP 2B、CYP 2 E、CYP 2F、CYP 4 B）定义见 猴子和人的肺。 重组P450（啮齿动物， 猴和人）将用NA、NN和IPO进行评估。 这项工作应 更好地理解了 啮齿动物、猴子和人类肺部对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活化。

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.