title: Genetic evidence for NAD(P)H:quinone oxidoreductase 1-catalyzed quinone reduction on passage through the mouse pulmonary circulation.
abstract: The quinones duroquinone (DQ) and coenzyme Q(1) (CoQ(1)) 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 CoQ(1) 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 CoQ(1) (60 μM) into the pulmonary arterial inflow of the isolated perfused lung and measurement of pulmonary venous effluent hydroquinone (DQH(2) or CoQ(1)H(2)). DQH(2) 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 CoQ(1)H(2) 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.
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lindemer
authors.forename: Robert D
authors.initials: RD
authors.lastname: Bongard
authors.forename: Raymond
authors.initials: R
authors.lastname: Hoffmann
authors.forename: Shelley
authors.initials: S
authors.lastname: Baumgardt
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Marilyn P
authors.initials: MP
authors.lastname: Merker
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000378:metabolism / Q000494:pharmacology; D001728:Dicumarol / Q000494:pharmacology; D008168:Lung / Q000378:metabolism; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D011652:Pulmonary Circulation / Q000187:drug effects; D014451:Ubiquinone / Q000378:metabolism / Q000494:pharmacology
chemical_list: D016227:Benzoquinones; D014451:Ubiquinone; D001728:Dicumarol; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; C025203:Ubiquinone Q1; C034257:duroquinone