Secondary radicals derived from chloramines of apolipoprotein B-100 contribute to HOCl-induced lipid peroxidation of low-density lipoproteins

TY - JOUR

T1 - Secondary radicals derived from chloramines of apolipoprotein B-100 contribute to HOCl-induced lipid peroxidation of low-density lipoproteins

AU - Hazell, L J

AU - Davies, Michael Jonathan

AU - Stocker, R

PY - 1999

Y1 - 1999

N2 - Oxidation of low-density lipoproteins (LDL) is thought to contribute to atherogenesis. Although there is increasing evidence for a role of myeloperoxidase-derived oxidants such as hypochlorite (HOCl), the mechanism by which HOCl modifies LDL remains controversial. Some studies report the protein component to be the major site of attack, whereas others describe extensive lipid peroxidation. The present study addresses this controversy. The results obtained are consistent with the hypothesis that radical-induced oxidation of LDL's lipids by HOCl is a secondary reaction, with most HOCl consumed via rapid, non-radical reaction with apolipoprotein B-100. Subsequent incubation of HOCl-treated LDL gives rise to lipid peroxidation and antioxidant consumption in a time-dependent manner. Similarly, with myeloperoxidase/H2O2/Cl- (the source of HOCl in vivo), protein oxidation is rapid and followed by an extended period of lipid peroxidation during which further protein oxidation does not occur. The secondary lipid peroxidation process involves EPR-detectable radicals, is attenuated by a radical trap or treatment of HOCl-oxidized LDL with methionine, and occurs less rapidly when the lipoprotein was depleted of alpha-tocopherol. The initial reaction of low concentrations of HOCl (400-fold or 800-fold molar excess) with LDL therefore seems to occur primarily by two-electron reactions with side-chain sites on apolipoprotein B-100. Some of the initial reaction products, identified as lysine-residue-derived chloramines, subsequently undergo homolytic (one-electron) reactions to give radicals that initiate antioxidant consumption and lipid oxidation via tocopherol-mediated peroxidation. The identification of these chloramines, and the radicals derived from them, as initiating agents in LDL lipid peroxidation offers potential new targets for antioxidative therapy in atherogenesis.

AB - Oxidation of low-density lipoproteins (LDL) is thought to contribute to atherogenesis. Although there is increasing evidence for a role of myeloperoxidase-derived oxidants such as hypochlorite (HOCl), the mechanism by which HOCl modifies LDL remains controversial. Some studies report the protein component to be the major site of attack, whereas others describe extensive lipid peroxidation. The present study addresses this controversy. The results obtained are consistent with the hypothesis that radical-induced oxidation of LDL's lipids by HOCl is a secondary reaction, with most HOCl consumed via rapid, non-radical reaction with apolipoprotein B-100. Subsequent incubation of HOCl-treated LDL gives rise to lipid peroxidation and antioxidant consumption in a time-dependent manner. Similarly, with myeloperoxidase/H2O2/Cl- (the source of HOCl in vivo), protein oxidation is rapid and followed by an extended period of lipid peroxidation during which further protein oxidation does not occur. The secondary lipid peroxidation process involves EPR-detectable radicals, is attenuated by a radical trap or treatment of HOCl-oxidized LDL with methionine, and occurs less rapidly when the lipoprotein was depleted of alpha-tocopherol. The initial reaction of low concentrations of HOCl (400-fold or 800-fold molar excess) with LDL therefore seems to occur primarily by two-electron reactions with side-chain sites on apolipoprotein B-100. Some of the initial reaction products, identified as lysine-residue-derived chloramines, subsequently undergo homolytic (one-electron) reactions to give radicals that initiate antioxidant consumption and lipid oxidation via tocopherol-mediated peroxidation. The identification of these chloramines, and the radicals derived from them, as initiating agents in LDL lipid peroxidation offers potential new targets for antioxidative therapy in atherogenesis.

KW - Apolipoprotein B-100

KW - Apolipoproteins B

KW - Chloramines

KW - Chlorides

KW - Cholesterol Esters

KW - Cyclic N-Oxides

KW - Electron Spin Resonance Spectroscopy

KW - Electrons

KW - Female

KW - Free Radicals

KW - Humans

KW - Hydrogen Peroxide

KW - Hydroxides

KW - Hypochlorous Acid

KW - Kinetics

KW - Lipid Peroxidation

KW - Lipoproteins, LDL

KW - Lysine

KW - Male

KW - Methionine

KW - Oxidants

KW - Peroxidase

KW - Tryptophan

KW - Vitamin E

M3 - Journal article

C2 - 10215584

SN - 0264-6021

VL - 339 ( Pt 3)

SP - 489

EP - 495

JO - Biochemical Journal

JF - Biochemical Journal

ER -