naphthoquinones and duroquinone

NAD(P)H/quinone acceptor oxidoreductase type 1 (QR1) protects cells from cytotoxic and neoplastic effects of quinones though two-electron reduction. Kinetic experiments, docking, and binding affinity calculations were performed on a series of structurally varied quinone substrates. A good correlation between calculated and measured binding affinities from kinetic determinations was obtained. The experimental and theoretical studies independently support a model in which quinones (with one to three fused aromatic rings) bind in the QR1 active site utilizing a pi-stacking interaction with the isoalloxazine ring of the FAD cofactor.

Topics: Animals; Anthraquinones; Benzoquinones; Binding Sites; Flavins; Humans; Kinetics; Models, Chemical; Models, Molecular; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Rats; Structure-Activity Relationship; Substrate Specificity; Thermodynamics; Tyrosine

The radical pair P700.+Q.- (P700 = primary electron donor, Q = quinone acceptor) in native photosystem I and in preparations in which the native acceptor (vitamin K1) is replaced by different quinones is investigated by pulsed EPR spectroscopy. In a two-pulse experiment, the light-induced radical pair causes an out-of-phase electron spin echo, showing an envelope modulation. From the modulation frequency, the dipolar coupling, and therefore the distance between the two cofactors, can be derived. The observation of nearly identical distances of about 25.4 A between P700.+ and Q.- in all preparations investigated here leads to the conclusion that the reconstituted quinones are bound to the native A1 binding pocket. Since the orientation of the reconstituted naphthoquinone relative to the axis joining P700.+ and Q*- differs drastically from that of the native vitamin K1, it cannot be bonded to the protein in the same way as the native acceptor. This implies that the function of A1 as an electron acceptor does not depend on the orientation or hydrogen bonding of the quinone.

Topics: Benzoquinones; Cyanobacteria; Electron Spin Resonance Spectroscopy; Naphthoquinones; Photosynthetic Reaction Center Complex Proteins; Quinones; Vitamin K 1

It was found that the activities of prooxidant enzymes (NAD(P)H oxidases and NAD(P)H:cytochrome c reductases) in bovine leukemia virus-transformed calf and lamb embryo kidney fibroblasts (lines Mi-18 and FLK) were by 1.25-18 times higher when compared to corresponding nontransformed calf cells. The activity of DT-diaphorase was also increased by about one order of magnitude in transformed cells. The activities of antioxidant enzymes were almost unchanged (superoxide dismutase), decreased by 13% or 53% (catalase) or increased by 25% or 90% (glutathione reductase) in Mi-18 or FLK cells, respectively. These changes of enzyme activity increased the toxicity of simple redox-cycling quinones (duroquinone, naphthazarin) towards transformed cells, but did not affect the toxicity of daunorubicin. The latter was most probably related to the inhibition of plasma membrane NADH dehydrogenase.

Topics: Animals; Benzoquinones; Cattle; Cell Line, Transformed; Cell Survival; Cell Transformation, Viral; Embryo, Mammalian; Ferricyanides; Fibroblasts; Kidney; Leukemia Virus, Bovine; Multienzyme Complexes; NAD(P)H Dehydrogenase (Quinone); NADH Dehydrogenase; NADH, NADPH Oxidoreductases; NADPH Oxidases; NADPH-Ferrihemoprotein Reductase; Naphthoquinones; Oxidation-Reduction; Quinones; Sheep

In guinea pig and rat cardiac tissue, redox cycling benzoquinones (2,5-dimethyl-p-benzoquinone and duroquinone) and naphthoquinones (menadione and 2,3-dimethoxy-1,4-naphthoquinone) generated superoxide anion (O2-.) both through one- and two-electron reductions, the generation being significantly greater in guinea pig than in rat tissue. In electrically driven left atria isolated from guinea pig and rat, menadione and 2,5-dimethyl-p-benzoquinone but not duroquinone caused a concentration-dependent positive inotropic effect. Unlike guinea pig, 2,3-dimethoxy-1,4-naphthoquinone had no effect in rat tissue. Naphthoquinones and 2,5-dimethyl-p-benzoquinone were more active in guinea pig than in rat tissue, their effect being dependent on the release of catecholamines from adrenergic stores. A linear relationship (r = 0.90) between the amount of O2-. generated by benzo- and naphthoquinones in guinea pig and rat heart and the extent of catecholamine-dependent positive inotropic effect was evident. An amount of O2-. higher than 600 nmol/g of tissue per min was calculated to be necessary to determine the catecholamine-mediated increase in contractility. Lipid peroxidation was not involved in quinone-induced catecholamine release.

Topics: Animals; Atrial Function; Benzoquinones; Catecholamines; Cyclohexenes; Free Radicals; Guinea Pigs; Heart Atria; In Vitro Techniques; Lipid Peroxidation; Microsomes; Mitochondria, Heart; Myocardial Contraction; Naphthoquinones; Oxidation-Reduction; Rats; Superoxides; Vitamin K

The effects of redox cycling, alkylating and mixed redox cycling/alkylating benzo- and naphthoquinones were examined in electrically driven guinea pig left atria. Cardiac microsomal and mitochondrial NAD(P)H-dependent metabolism of the quinones and consequent generation of superoxide anion (O2.-) were also measured. Mixed redox cycling/alkylating 2-methyl-1,4-naphthoquinone, redox cycling 2,3-dimethoxy-1,4-naphthoquinone and alkylating p-benzoquinone determined concentration-dependent positive inotropic responses, whereas redox cycling 2,3,5,6-tetramethyl-p-benzoquinone had no effect. The positive inotropic effect of 2,3-dimethoxy-1,4-naphthoquinone was completely catecholamine-mediated, that of 2-methyl-1,4-naphthoquinone was approximately 70% adrenergic and 30% direct. p-Benzoquinone acted directly on heart muscle. In time, quinones with alkylating properties caused increases in the resting force of atria, whereas redox cycling quinones did not produce toxic effects. Mitochondrial NADH-oxidoreductase accounted for 90 to 95% of the metabolism of all quinones, whereas the contribution of the microsomal pathway was negligible. Considerable amounts of O2.- were produced by mitochondrial biotransformation of 2-methyl-1,4-naphthoquinone and 2,3-dimethoxy-1,4-naphthoquinone but not of 2,3,5,6-tetramethyl-p-benzoquinone and p-benzoquinone, suggesting a kind of relation between O2.- generation and the release of catecholamines.

Topics: Alkylating Agents; Animals; Atrial Function, Left; Benzoquinones; Guinea Pigs; Heart; Heart Atria; Mice; Microsomes; Mitochondria, Heart; Myocardial Contraction; NADH, NADPH Oxidoreductases; Naphthoquinones; Oxidation-Reduction; Quinones; Substrate Cycling; Superoxides; Vitamin K

Incorporation of 32P from [gamma-32P]ATP into endogenous proteins, added histone and the copolymers Glu 80 Tyr 20 by rat liver plasma membranes was markedly increased by several naphthoquinones, including menadione. This stimulation was most marked with Glu 80 Tyr 20, has an absolute requirement for either dithiothreitol or reduced glutathione, and was inhibited by superoxide dismutase, catalase, and desferrioxamine to varying degrees depending on the quinones used. Their effectiveness in stimulating the apparent tyrosine-specific protein phosphorylation correlated with the rates of DTT-dependent redox cycling measured by oxygen consumption. Increased protein phosphorylation was also seen with particulate fractions isolated from hepatocytes incubated with quinones. A free radical-mediated mechanism is suggested for the quinone stimulation of protein phosphorylation.

Topics: Adenosine Triphosphate; Animals; Benzoquinones; Cell Membrane; Deferoxamine; Free Radicals; Hydroquinones; Liver; Naphthoquinones; Oxidation-Reduction; Oxygen; Oxygen Consumption; Protein-Tyrosine Kinases; Quinones; Rats; Structure-Activity Relationship; Superoxide Dismutase; Vitamin K