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Effect of chronic hyperoxic exposure on duroquinone reduction in adult rat lungs

Departments of ¹Biomedical Engineering, ²Mathematics, Statistics, and Computer Science, Marquette University; Departments of ³Pulmonary and Critical Care Medicine, ⁴Anesthesiology, and ⁵Pharmacology/Toxicology, Medical College of Wisconsin, and ⁶Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin

Submitted 8 February 2005 ; accepted in final form 23 June 2005

NAD(P)H:quinone oxidoreductase 1 (NQO1) plays a dominant role in the reduction of the quinone compound 2,3,5,6-tetramethyl-1,4-benzoquinone (duroquinone, DQ) to durohydroquinone (DQH₂) on passage through the rat lung. Exposure of adult rats to 85% O₂ for 7 days stimulates adaptation to the otherwise lethal effects of >95% O₂. The objective of this study was to examine whether exposure of adult rats to hyperoxia affected lung NQO1 activity as measured by the rate of DQ reduction on passage through the lung. We measured DQH₂ appearance in the venous effluent during DQ infusion at different concentrations into the pulmonary artery of isolated perfused lungs from rats exposed to room air or to 85% O₂. We also evaluated the effect of hyperoxia on vascular transit time distribution and measured NQO1 activity and protein in lung homogenate. The results demonstrate that exposure to 85% O₂ for 21 days increases lung capacity to reduce DQ to DQH₂ and that NQO1 is the dominant DQ reductase in normoxic and hyperoxic lungs. Kinetic analysis revealed that 21-day hyperoxia exposure increased the maximum rate of pulmonary DQ reduction, V_max, and the apparent Michaelis-Menten constant for DQ reduction, K_ma. The increase in V_max suggests a hyperoxia-induced increase in NQO1 activity of lung cells accessible to DQ from the vascular region, consistent qualitatively but not quantitatively with an increase in lung homogenate NQO1 activity in 21-day hyperoxic lungs. The increase in K_ma could be accounted for by 40% increase in vascular transit time heterogeneity in 21-day hyperoxic lungs.

mathematical modeling; NAD(P)H:quinone oxidoreductase; mitochondrial electron transport; pulmonary endothelium; oxidative stress

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