TOXICOLOGY OF NASAL GAS DEPOSITION IN FIVE SPECIES

五种物种鼻气沉积的毒理学

• 批准号: 3251238
• 负责人: JOHN B MORRIS
• 金额: $ 13.55万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-03-01 至 1991-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3251238
• 关键词: acetone; air sampling /monitoring; alcohol dehydrogenase; drug administration rate /duration; environmental toxicology; enzyme mechanism; enzyme structure; ethanol; gas chromatography; laboratory rat; mathematical model; pollution related respiratory disorder; pulmonary respiration; respiratory epithelium; respiratory gas transport; respiratory toxin; species difference; statistics /biometry; unspecific monooxygenase

It has recently been discovered that the nasal mucosa is rich in xenobiotic metabolizing enzymes, however, their quantitative importance in the in vivo setting is not known. The primary aim of the proposed research is to provide quantitative information on the extent to which inhaled vapors are metabolized in nasal tissues in vivo. Towards this end the deposition of nine vapors will be measured in the surgically isolated upper respiratory tract of anesthetized Fischer 344 rats and golden Syrian hamsters. The selected vapors are substrates for either alcohol dehydrogenase, carboxylesterase or mixed function oxidases, enzymes known to be present in the nasal mucosa in high levels. The extent of metabolism will be estimated by mathematic modeling of the deposition data and by measurement of deposition in naive and metabolic inhibitor-pretreated animals. Metabolism in the nasal mucosa has the potential to be of critical and fundamental importance in the respiratory and systemic toxicity of inhaled vapors. Metabolism at the site of entry results in high local concentrations of metabolite(s) and limits the amount of parent compound available for absorption into the general circulation. Nasal metabolism also enhances deposition of inhaled vapors in the site and, thus, spares the lungs from their toxic effects. The limited information currently available on the disposition of deposited vapors suggests 50% or more of the deposited burden may be metabolized in situ in nasal tissues. Because it may exert a profound effect on overall toxicity, quantitative knowledge on the extent of metabolism at the site of entry is essential for a complete understanding of the toxicity of any substance. By quantitating and providing insights into the important factors involved in this processs, the proposed research will significantly advance our knowledge of fundamentally important principles of inhalation toxicology and in the long-term will enhance our ability to predict and interpret the regional respiratory and systemic toxicity of inhaled vapors.

最近发现鼻粘膜丰富 然而，异生物生物代谢酶的定量 在体内环境中的重要性尚不清楚。 主要目的 拟议的研究是提供有关的定量信息 在鼻腔中代谢吸入蒸气的程度 组织在体内。 为此结束九个蒸气的沉积 将在手术隔离的上呼吸道中测量 麻醉的Fischer 344只老鼠和金叙利亚仓鼠。 这 选定的蒸气是任何一种酒精脱氢酶的底物， 羧酸酯酶或混合功能氧化酶，已知的酶 在高水平的鼻粘膜中存在。 程度 代谢将通过数学建模来估算 沉积数据以及通过测量天真的沉积 代谢抑制剂预测的动物。 鼻粘膜中的代谢有可能至关重要 以及在呼吸道和系统性中的基本重要性 吸入蒸气的毒性。 入境结果现场的代谢 在高局部浓度的代谢物中，并限制了 可用于吸收的母体化合物的量 一般循环。 鼻形代谢也增强了 在现场吸入蒸气，从而使肺部从其 有毒作用。 当前可用的有限信息 沉积蒸气的处置表明50％或更多 沉积负担可能会在鼻组织中代谢。 因为它可能对整体毒性产生深远的影响，所以 关于代谢程度的定量知识 进入对于完全了解的毒性至关重要 任何实质。 通过量化并提供有关 拟议的研究中涉及的重要因素 将大大促进我们从根本上了解 吸入毒理学的重要原则以及长期 将增强我们预测和解释区域的能力 吸入蒸气的呼吸和全身毒性。