XENOBIOTIC METABOLISM AND PARAQUAT TOXICITY

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，由许多环境造成的组织损伤 遇到化学物质，与衰老相关的肺保护力丧失 机制，以及细胞活力的丧失。形态上的变化 在氧化剂诱导的肺损伤的许多模型中都有很好的描述； 然而，关于潜在生物化学的信息要少得多。 机械装置。活性氧在几个方面的作用正在调查中 而且似乎是氧化剂毒性的一个共同因素。这个 细胞能量学与活性底物代谢的相互作用 Long一直没有得到多少关注。然而，最近来自这一点的证据 实验室表明，细胞氧化还原电位的变化可能会导致 通过百草枯与异源代谢的相互作用，可能是 至少一种氧化剂所致肺损伤的机制。 百草枯中毒是这类肺损伤的一个很好的模型。这 化学物质在哺乳动物体内不会代谢，因此代谢物的毒性 这不是一个复杂的因素。组织病理学，给药方案，以及 毒性的物种多样性都得到了很好的证实。几个 初步研究结果强烈表明，某些细胞的改变 生物能反应先于形态变化，因此可能是 导致其他重要细胞丢失的主要致病事件 功能，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，从而提供 评估组织氧化还原能力在加速中的作用的机会 毒性。 百草枯与异体代谢相互作用的研究 抗坏血酸的存在和缺失将检验这样一种假设： 相互作用导致细胞还原能力不平衡，这是 最终会产生细胞毒性。

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.