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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003340-02
Application #
3250542
Study Section
Toxicology Study Section (TOX)
Project Start
1985-01-01
Project End
1987-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of South Florida
Department
Type
Schools of Medicine
DUNS #
City
Tampa
State
FL
Country
United States
Zip Code
33612
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