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1 Department of Biomedical Engineering, Marquette University, Milwaukee, WI, USA; Department of Pulmonary and Critical Care Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
2 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
3 Department of Biomedical Engineering, Marquette University, Milwaukee, WI, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA; Research Service, Zablocki VA Medical Center, Milwaukee, WI, USA
4 School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO, USA
5 Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Pharmacology/Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA; Research Service, Zablocki VA Medical Center, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: audis{at}mu.edu.
The lungs have a substantial capacity for influencing the redox status of redox active plasma constituents. The objective of this study was to examine some aspects of the kinetics and mechanisms that can determine the pulmonary disposition of redox active compounds during passage through the pulmonary circulation. Experiments were carried out on lungs from rats and mice using 2,3,5,6-tetramethyl-1,4-benzoquinone (duroquinone, DQ) as a model amphipathic quinone reductase substrate. The primary measurements were of DQ and durohydroquinone (DQH2) concentrations in the lung venous effluent after injecting, or while infusing, DQ or DQH2 into the pulmonary arterial inflow. The maximum net rates of DQ reduction to DQH2 in the rat and mouse lungs were about 4.9 and 2.5 µmole/min/gram dry lung wt, respectively. The net reduction DQ rate was apparently the result of freely permeating access of DQ and DQH2 to tissue sites of redox reactions, dominated by dicumarol sensitive DQ reduction to DQH2 and cyanide sensitive DQH2 re-oxidation back to DQ. The dicumarol sensitivity along with immuno-detectable expression of NAD(P)H: quinone oxidoreductase 1 (NQO1) in the rat lung tissue suggest that the dominant site of DQ reduction is cytoplasmic NQO1. The effect of cyanide on DQH2 oxidation suggests that the dominant site of oxidation is complex III of the mitochondrial electron transport chain. Envisioning DQ as a model compound for examining the disposition of amphipathic NQO1 substrates in the lungs, the results are consistent with a role for lung NQO1 in determining the redox status of such compounds in the circulation. In the case of DQ, the effect is conversion of a redox cycling, oxygen activating, quinone into its stable hydroquinone during passage through the pulmonary circulation.
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