title: When and why a water-soluble antioxidant becomes pro-oxidant during copper-induced low-density lipoprotein oxidation: a study using uric acid.
abstract: The inclusion of uric acid in the incubation medium during copper-induced low-density lipoprotein (LDL) oxidation exerted either an antioxidant or pro-oxidant effect. The pro-oxidant effect, as mirrored by an enhanced formation of conjugated dienes, lipid peroxides, thiobarbituric acid-reactive substances and increase in negative charge, occurred when uric acid was added late during the inhibitory or lag phase and during the subsequent extensive propagation phase of copper-stimulated LDL oxidation. The pro-oxidant effect of uric acid was specific for copper-induced LDL oxidation and required the presence of copper as either Cu(I) or Cu(II). In addition, it became much more evident when the copper to LDL molar ratio was below a threshold value of approx. 50. In native LDL, the shift between the antioxidant and the pro-oxidant activities was related to the availability of lipid hydroperoxides formed during the early phases of copper-promoted LDL oxidation. The artificial enrichment of isolated LDL with alpha-tocopherol delayed the onset of the pro-oxidant activity of uric acid and also decreased the rate of stimulated lipid peroxidation. However, previous depletion of alpha-tocopherol was not a prerequisite for unmasking the pro-oxidant activity of uric acid, since this became apparent even when alpha-tocopherol was still present in significant amounts (more than 50% of the original values) in LDL. These results suggest, irrespective of the levels of endogenous alpha-tocopherol, that uric acid may enhance LDL oxidation by reducing Cu(II) to Cu(I), thus making more Cu(I) available for subsequent radical decomposition of lipid peroxides and propagation reactions.
authors.affiliation: Department of Medical Sciences, University of Piemonte Orientale 'A. Avogadro', Novara, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Bagnati
authors.forename: C
authors.initials: C
authors.lastname: Perugini
authors.forename: C
authors.initials: C
authors.lastname: Cau
authors.forename: R
authors.initials: R
authors.lastname: Bordone
authors.forename: E
authors.initials: E
authors.lastname: Albano
authors.forename: G
authors.initials: G
authors.lastname: Bellomo
mesh_terms: D000578:Amidines / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology; D002412:Cations / Q000494:pharmacology; D002788:Cholesterol Esters / Q000378:metabolism; D003300:Copper / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006878:Hydroxides / Q000378:metabolism; D054833:Isoindoles; D008054:Lipid Peroxides / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008084:Lipoxygenase / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D012995:Solubility; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014527:Uric Acid / Q000494:pharmacology*; D014810:Vitamin E / Q000378:metabolism / Q000494:pharmacology; D014867:Water / Q000378:metabolism*
chemical_list: D000578:Amidines; D000975:Antioxidants; D001393:Azoles; D002412:Cations; D002788:Cholesterol Esters; D006878:Hydroxides; D054833:Isoindoles; D008054:Lipid Peroxides; D008077:Lipoproteins, LDL; D016566:Organoselenium Compounds; D016877:Oxidants; D017392:Thiobarbituric Acid Reactive Substances; D014867:Water; D014810:Vitamin E; D014527:Uric Acid; C042986:ebselen; C021976:cholesteryl linoleate; C046728:2,2'-azobis(2-amidinopropane); D003300:Copper; D004492:Edetic Acid; D006861:Hydrogen Peroxide; D008084:Lipoxygenase; D005978:Glutathione