Two-electron reduction of quinones by rat liver NAD(P)H:quinone oxidoreductase: quantitative structure–activity relationships

Anusevičius, Žilvinas; Šarlauskas, Jonas; Čėnas, Narimantas

doi:10.1016/s0003-9861(02)00273-4

Cited by 51 publications

(67 citation statements)

References 52 publications

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“…The propensity for any given concentration of CoQ 1 to act as an NQO1 electron acceptor in intact rat, but not mouse, lung or intact bovine pulmonary arterial endothelial cells may be attributable to species differences in electron acceptor substrate specificity or activity (18). The preference for DQ over CoQ 1 as an NQO1 electron acceptor is suggested by structure-activity studies showing that quinones with van der Waals volumes of Ͻ200 Å (162.9 Å for DQ and 243.96 Å for CoQ 1 ) have been observed to act as relatively "fast" NQO1 substrates (high K cat /K m ) (3,28,41). In any case, the differential impact of intact mouse and rat lung NQO1 on CoQ 1 illustrates the concept that quinone fate in the lung depends on the properties of the substances themselves (e.g., propensity to act as an electron acceptor for any given reductase), as well as the properties of the pulmonary endothelium and lung tissue (e.g., relative activities and complement of available redox enzymes).…”

Section: Discussionmentioning

confidence: 99%

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

Lindemer¹,

Bongard

Hoffmann

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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Lindemer BJ, Bongard RD, Hoffmann R, Baumgardt S, Gonzalez FJ, Merker MP. Genetic evidence for NAD(P)H: quinone oxidoreductase 1-catalyzed quinone reduction on passage through the mouse pulmonary circulation. Am J Physiol Lung Cell Mol Physiol 300: L773-L780, 2011. First published February 4, 2011 doi:10.1152/ajplung.00394.2010.-The quinones duroquinone (DQ) and coenzyme Q 1 (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 CoQ 1 reductases. Since inhibitors have nonspecific effects, the goal was to use Nqo1-null (NQO1 Ϫ / Ϫ ) mice to evaluate DQ as an NQO1 probe in the lung. Lung homogenate cytosol NQO1 activities were 97 Ϯ 11, 54 Ϯ 6, and 5 Ϯ 1 (SE) nmol dichlorophenolindophenol reduced · min Ϫ1 · mg protein Ϫ1 for NQO1 ϩ/ϩ , NQO1 ϩ/Ϫ , and NQO1 Ϫ/Ϫ lungs, respectively. Intact lung quinone reduction was evaluated by infusion of DQ (50 M) or CoQ1 (60 M) into the pulmonary arterial inflow of the isolated perfused lung and measurement of pulmonary venous effluent hydroquinone (DQH2 or CoQ 1H2). DQH2 efflux rates for NQO1 ϩ/ϩ , NQO1 ϩ/Ϫ , and NQO1 Ϫ/Ϫ lungs were 0.65 Ϯ 0.08, 0.45 Ϯ 0.04, and 0.13 Ϯ 0.05 (SE) mol · min Ϫ1 · g dry lung Ϫ1 , respectively. DQ reduction in NQO1 ϩ/ϩ lungs was inhibited by 90 Ϯ 4% with dicumarol; there was no inhibition in NQO1 Ϫ/Ϫ lungs. There was no significant difference in CoQ1H2 efflux rates for NQO1 ϩ/ϩ and NQO1 Ϫ/Ϫ 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. knockout mice; lung metabolism; duroquinone; isolated perfused mouse lung; coenzyme Q THE PULMONARY ENDOTHELIUM and lung tissue participate in altering the redox status and disposition of certain redox-active compounds as they pass through the pulmonary circulation (4 -7, 9). This function is carried out by redox enzymes at the pulmonary endothelial surface and within pulmonary endothelial and other lung cells. Since the redox forms of such compounds have different propensities to permeate tissues and carry out pro-and/or antioxidant functions, passage of these compounds through the pulmonary circulation has the potential to influence their dispositions, concentrations, and bioactivities within the pulmonary vessels and lung itself, as well as in downstream organs and vessels.Quinones comprise a class of redox-active compounds having a wide range of physical and chemical properties, and a number of mammalian enzymes have quinone reductase activity (13). Therefore, quinones are useful for probing lung redox processes that affect their disposition in the blood. We have used the amphipathic quinone duroquinone (DQ) as one model compound for st...

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Section: Discussionmentioning

confidence: 99%

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

Lindemer¹,

Bongard

Hoffmann

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…With respect to the relative specificity of NQO1 for the two quinones, although CoQ 1 acts as a substrate for isolated NQO1, a marked preference was observed for DQ as an NQO1 electron acceptor in the intact pulmonary endothelial cells in the present study. This might have been anticipated based on quantitative structure activity studies showing that quinones with van der Waals volume of Ͻ200 Å (DQ, 162.9 Å; CoQ1, 243.96 Å) behave as relatively "fast" NQO1 substrates (high K cat /K m ) (1,41). Thus the basis for the propensity for CoQ 1 to act as an NQO1 substrate in studies of various other cell types is not known and may be attributable in part to species differences in NQO1 electron acceptor preference (17).…”

Section: Discussionmentioning

confidence: 99%

Role of mitochondrial electron transport complex I in coenzyme Q₁reduction by intact pulmonary arterial endothelial cells and the effect of hyperoxia

Merker¹,

Audi²,

Lindemer³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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The objective was to determine the impact of intact normoxic and hyperoxia-exposed (95% O(2) for 48 h) bovine pulmonary arterial endothelial cells in culture on the redox status of the coenzyme Q(10) homolog coenzyme Q(1) (CoQ(1)). When CoQ(1) (50 microM) was incubated with the cells for 30 min, its concentration in the medium decreased over time, reaching a lower level for normoxic than hyperoxia-exposed cells. The decreases in CoQ(1) concentration were associated with generation of CoQ(1) hydroquinone (CoQ(1)H(2)), wherein 3.4 times more CoQ(1)H(2) was produced in the normoxic than hyperoxia-exposed cell medium (8.2 +/- 0.3 and 2.4 +/- 0.4 microM, means +/- SE, respectively) after 30 min. The maximum CoQ(1) reduction rate for the hyperoxia-exposed cells, measured using the cell membrane-impermeant redox indicator potassium ferricyanide, was about one-half that of normoxic cells (11.4 and 24.1 nmol x min(-1) x mg(-1) cell protein, respectively). The mitochondrial electron transport complex I inhibitor rotenone decreased the CoQ(1) reduction rate by 85% in the normoxic cells and 44% in the hyperoxia-exposed cells. There was little or no inhibitory effect of NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibitors on CoQ(1) reduction. Intact cell oxygen consumption rates and complex I activities in mitochondria-enriched fractions were also lower for hyperoxia-exposed than normoxic cells. The implication is that intact pulmonary endothelial cells influence the redox status of CoQ(1) via complex I-mediated reduction to CoQ(1)H(2), which appears in the extracellular medium, and that the hyperoxic exposure decreases the overall CoQ(1) reduction capacity via a depression in complex I activity.

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“…Each of these active sites is composed of residues from both polypeptide chains [77]. The enzyme catalyses the NADH or NADPH-dependent reduction of a variety of organic compounds, including quinones [78][79][80][81][82]. Its cellular role is not wholly clear, but it seems likely that NQO1 participates in the detoxification of xenobiotic compounds and also in the cycling of quinones in the cell [75].…”

Section: Dicoumarol Also Inhibits Nqo1mentioning

confidence: 99%

Dicoumarol: A Drug which Hits at Least Two Very Different Targets in Vitamin K Metabolism

Timson

2017

CDT

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Dicoumarol, a symmetrical biscoumarin can be considered as the "parent" of the widely used anticoagulant drug, warfarin. The discovery of dicoumarol's bioactive properties resulted from an investigation into a mysterious cattle disease in the 1940s. It was then developed as a pharmaceutical, but was superseded in the 1950s by warfarin. Both dicoumarol and warfarin antagonise the blood clotting process through inhibition of vitamin K epoxide reductase (VKOR). This blocks the recycling of vitamin K and prevents the γ-carboxylation of glutamate residues in clotting factors.VKOR is an integral membrane protein and our understanding of the molecular mechanism of action of dicoumarol and warfarin is hampered by the lack of a three dimensional structure. There is consequent controversy about the membrane topology of VKOR, the location of the binding site for coumarin inhibitors and the mechanism of inhibition by these compounds. Dicoumarol (and warfarin) also inhibit a second enzyme, NAD(P)H quinone oxidoreductase 1 (NQO1). This soluble, cytoplasmic enzyme may also play a minor role in the recycling of vitamin K. However, its main cellular roles as an enzyme appear to be detoxification and the prevention of the build-up of reactive oxygen species. NQO1 is well characterised biochemically and structurally. Consequently, structurebased drug design has identified NQO1 inhibitors which have potential for the development of anticancer drugs. Many of these compounds are structurally related to dicoumarol and some have reduced "off target" effects. Therefore, it is possible that dicoumarol will become the "parent" of a second group of drugs.

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Two-electron reduction of quinones by rat liver NAD(P)H:quinone oxidoreductase: quantitative structure–activity relationships

Cited by 51 publications

References 52 publications

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

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

Role of mitochondrial electron transport complex I in coenzyme Q₁reduction by intact pulmonary arterial endothelial cells and the effect of hyperoxia

Dicoumarol: A Drug which Hits at Least Two Very Different Targets in Vitamin K Metabolism

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Two-electron reduction of quinones by rat liver NAD(P)H:quinone oxidoreductase: quantitative structure–activity relationships

Cited by 51 publications

References 52 publications

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

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

Role of mitochondrial electron transport complex I in coenzyme Q1reduction by intact pulmonary arterial endothelial cells and the effect of hyperoxia

Dicoumarol: A Drug which Hits at Least Two Very Different Targets in Vitamin K Metabolism

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Role of mitochondrial electron transport complex I in coenzyme Q₁reduction by intact pulmonary arterial endothelial cells and the effect of hyperoxia