Kuchmenko O. Biochemical properties of ubiquinone function under pathological conditions

The present dissertational study is dedicated to the investigation of biochemical properties of uniquinone function under pathological conditions (E-hypovitaminosis, adrenaline and doxorubicin injury, tumor growth), and also aging. In studies with radioactive labeled tyrosine it is shown that dietary deprivation of vitamin A and E leads to a decrease in intensity of ubiquinone biosynthesis in rats' liver tissue and to its intracellular redistribution. Providing intact animals and animals with E-hypovitaminosis with complexes of precursors and modulators of ubiquinone biosynthesis (4-hydroxybenzoic acid, methionine, alfa-tocopherylacetate, ascorbic acid, panthotenic acid, folic acid, magnesium sulfate, dmethyl sulfoxide) is effective for increase of ubiquinone content and for activization of ubiquinone-depending enzyme systems - NADH-ubiquinone-oxidoreductase and succinate-ubiquinone-oxidoreductase. Preventive and/or subsequent application of complexes of precursors and modulators of ubiquinone biosynthesis under the adrenaline treatment reduces free-radical lipid and protein peroxidation intensity, decreases in sensitivity of mitochondrial permeability transition pore to inductors of its opening, but increases superoxide dismutase activity and improves activities of the mitochondrial electron-transport chain complexes I, II and IV. These complexes can act as effective anti-hypoxic remedies that promote normalization of the energy metabolism in ischemic heart. The obtained results demonstrate that administration of complexes of precursors and modulators of ubiquinone biosynthesis caused the increase of ubiquinone and vitamin E content, correction of functional activity of mitochondrial electron-transport chain enzyme complexes I, II and IV, the decrease in intensity of lipid and protein free-radical peroxidation in heart and liver mitochondria and tissues, and the decrease in sensitivity of mitochondrial permeability transition pore to inductors of its opening in old rats' heart mitochondria. Application of these complexes contributes to the protective effects due to the reduction in the ischemia-reperfusion injury in old rat hearts. This effect exerts in the restoration of myocardial contractile function and coronary flow as well as in the decrease of the end diastolic pressure and in the oxygen cost of the heart work. This approach may be used for correction of mitochondrial dysfunction under various pathologies of cardiovascular system and in aging. In the series of studies on rats treated with doxorubicin the administration of complexes of precursors and modulators of ubiquinone biosynthesis and ubiquinone-10 leads to significant decrease in tissue matrix metalloproteinase-2 and -9 activities, superoxide radical and NO level, intensity of lipid and protein free-radical peroxidation, sensitivity of mitochondrial permeability transition pore to inductors of its opening, increase of ubisemiquinone content and normalization of mitochondrial electron-transport chain function, which may lead to notable reduction of doxorubicin toxicity. Also the protective effect of these complexes on endoplasmic reticulum is demonstrated. Treatment of experimental animals with Guerin's carcinoma and Walker-256 mammary carcinoma with complexes of precursors and modulators of ubiquinone biosynthesis and ubiquinone-10 in addition to doxorubicin administration results in increase of its antitumor activity of doxorubicin. These data provide ground for application of these biologically active substances in cancer chemotherapy for reducing the incidence of varipus types of doxorubicin toxicity.