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Genetic evidence for NAD(P)H:quinone oxidoreductase 1-catalyzed quinone reduction on passage through the mouse pulmonary circulation

By Brian J. Lindemer, Robert D. Bongard, Raymond Hoffmann, Shelley Baumgardt, Frank J. Gonzalez and Marilyn P. Merker


The quinones duroquinone (DQ) and coenzyme Q1 (CoQ1) and quinone reductase inhibitors have been used to identify reductases involved in quinone reduction on passage through the pulmonary circulation. In perfused rat lung, NAD(P)H:quinone oxidoreductase 1 (NQO1) was identified as the predominant DQ reductase and NQO1 and mitochondrial complex I as the CoQ1 reductases. Since inhibitors have nonspecific effects, the goal was to use Nqo1-null (NQO1−/−) mice to evaluate DQ as an NQO1 probe in the lung. Lung homogenate cytosol NQO1 activities were 97 ± 11, 54 ± 6, and 5 ± 1 (SE) nmol dichlorophenolindophenol reduced·min−1·mg protein−1 for NQO1+/+, NQO1+/−, and NQO1−/− lungs, respectively. Intact lung quinone reduction was evaluated by infusion of DQ (50 μM) or CoQ1 (60 μM) into the pulmonary arterial inflow of the isolated perfused lung and measurement of pulmonary venous effluent hydroquinone (DQH2 or CoQ1H2). DQH2 efflux rates for NQO1+/+, NQO1+/−, and NQO1−/− lungs were 0.65 ± 0.08, 0.45 ± 0.04, and 0.13 ± 0.05 (SE) μmol·min−1·g dry lung−1, respectively. DQ reduction in NQO1+/+ lungs was inhibited by 90 ± 4% with dicumarol; there was no inhibition in NQO1−/− lungs. There was no significant difference in CoQ1H2 efflux rates for NQO1+/+ and NQO1−/− lungs. Differences in DQ reduction were not due to differences in lung dry weights, wet-to-dry weight ratios, perfusion pressures, perfused surface areas, or total DQ recoveries. The data provide genetic evidence implicating DQ as a specific NQO1 probe in the perfused rodent lung

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Publisher: American Physiological Society
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