XENOBIOTIC METABOLISM AND PARAQUAT TOXICITY

异生物代谢和百草枯毒性

• 批准号: 3250540
• 负责人: MARK R MONTGOMERY
• 金额: $ 7.82万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-01-01 至 1987-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3250540
• 关键词: NAD(H) phosphate; ascorbate; cytotoxicity; histology; lung disorder; oxidation reduction reaction; paraquat; pesticide interaction; pollution related respiratory disorder; respiratory toxin; spectrometry; toxin metabolism; unspecific monooxygenase

Oxidative lung injury is a broad toxicological problem which includes several specific drug toxicities, tissue damage by numerous environmentally encountered chemicals, the aging related loss of pulmonary protective mechanisms, and loss of cellular viability. The morphological alterations occurring in many models of oxidant-induced lung injury are well described; however, much less information is available on underlying biochemical mechanisms. The role of activated oxygen is under investigation in several laboratories and appears to be a common factor in oxidant toxicity. The interaction of cellular energetics and active substrate metabolism in the lung has received scant attention. However, recent evidence from this laboratory suggests that changes in cellular redox potential may result from paraquat interaction with xenobiotic metabolism and may be a causative mechanism in at least one model of oxidant-induced lung injury. Paraquat toxicity is an excellent model for this type of lung damage. This chemical is not metabolized in mammalian systems, so metabolite toxicity is not a complicating factor. The histopathology, dosing regimens, and species variability of the toxicity are all well established. Several preliminary findings strongly suggest that alterations in certain cellular bioenergetic reactions precede morphological changes and, therefore, may be primary causative events which lead to loss of other vital cellular functions and ultimately, lead to cell death. Using ascorbic acid in combination with paraquat potentiates the toxicity which provide an opportunity to evaluate the role of tissue redox capability in accelerated toxicity. Investigation of the interaction of xenobiotic metabolism with paraquat in the absence and presence of ascorbic acid will test the hypothesis that the interaction results in imbalances in cellular reduction capacity which is ultimately cytotoxic.

氧化性肺损伤是一个广泛的毒理学问题，包括 几种特定的药物毒性，组织损伤，由许多环境 遇到化学物质，老化相关的肺保护功能丧失 机制和细胞活力的丧失。 的形态学改变 在许多氧化剂诱导的肺损伤模型中发生的肺损伤已得到很好的描述; 然而，关于潜在的生物化学的信息要少得多， 机制等 活性氧的作用正在研究中的几个 实验室和似乎是一个共同的因素在氧化剂毒性。 的 细胞能量学和活性底物代谢的相互作用 肺很少受到关注。 然而，最近的证据表明， 实验室表明，细胞氧化还原电位的变化可能导致 百草枯与异生物质代谢的相互作用， 在至少一种氧化剂诱导的肺损伤模型中的作用机制。 百草枯中毒是这类肺损伤的极好模型。 这 化学品在哺乳动物系统中不代谢，因此代谢物毒性 不是一个复杂的因素。 组织病理学、给药方案和 毒性的物种变异性都已得到充分证实。 几 初步研究结果强烈表明，某些细胞的变化， 生物能反应先于形态学变化，因此， 导致其他重要细胞损失的主要致病事件 功能并最终导致细胞死亡。 使用抗坏血酸 与百草枯联合使用会增强毒性， 有机会评估组织氧化还原能力在加速 毒性 百草枯与异源物质代谢的相互作用研究 抗坏血酸的存在和不存在将检验以下假设： 相互作用导致细胞还原能力的不平衡， 最后是细胞毒性。