Mechanisms of copper- and iron-dependent oxidative modification of human low density lipoprotein.
Oxidative modification of low density lipoprotein (LDL) has been suggested as a causal step in atherosclerosis, and both redox-active transition metal ions and superoxide (O2.-) have been implicated in this process. In order to determine the mechanisms of metal ion-dependent oxidation of LDL in the presence of O2.-, LDL was exposed to hypoxanthine (HX) and purified xanthine oxidase (XO) without and with added CuCl2 or Fe(3+)-citrate. Production of O2.- and hydrogen peroxide (H2O2) at pH 7.4 by the HX/XO system in the absence of metal ions was not sufficient to oxidize LDL. Preincubation of LDL with Cu2+ or Fe(3+)-citrate with subsequent removal of metal ions not tightly bound to the lipoprotein did not enable the HX/XO system to oxidize LDL. However, incubation of LDL with HX/XO and Cu2+ resulted in extensive modification of LDL. Exposure of LDL to Cu2+ alone also led to extensive modification, although the LDL was initially free of detectable amounts of lipid hydroperoxides (LOOH), i.e., < 0.005 molecules of LOOH per LDL particle. Although HX/XO and Cu2+ did not produce detectable amounts of O2.- or aqueous hydroxyl radicals (HO.), oxidation of LDL under these conditions was partially inhibited by superoxide dismutase, and completely inhibited by the HO. scavenger thiourea. In contrast to Cu(2+)-mediated oxidation of LDL, oxidation mediated by Fe(3+)-citrate was strictly dependent upon O2.-, as it was abolished by omission of the HX/XO system or by addition of superoxide dismutase to this system.(ABSTRACT TRUNCATED AT 250 WORDS)
Lynch
S M
SM
Department of Nutrition, Harvard School of Public Health, Boston, MA 02115.
Frei
B
B
D001393:Azoles / Q000494:pharmacology; D003300:Copper / Q000378:metabolism / Q000494:pharmacology*; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000378:metabolism; D007501:Iron / Q000378:metabolism / Q000494:pharmacology*; D054833:Isoindoles; D015227:Lipid Peroxidation; D008077:Lipoproteins, LDL / Q000097:blood*; D016566:Organoselenium Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D013481:Superoxides / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D001393:Azoles; D007042:Hypoxanthines; D054833:Isoindoles; D008077:Lipoproteins, LDL; D016566:Organoselenium Compounds; D013481:Superoxides; D019271:Hypoxanthine; D017665:Hydroxyl Radical; C042986:ebselen; D003300:Copper; D006861:Hydrogen Peroxide; D007501:Iron; D014969:Xanthine Oxidase; D005978:Glutathione