Hypochlorous acid-mediated oxidation of lipid components and antioxidants present in low-density lipoproteins: absolute rate constants, product analysis, and computational modeling
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Hypochlorous acid-mediated oxidation of lipid components and antioxidants present in low-density lipoproteins : absolute rate constants, product analysis, and computational modeling. / Pattison, David I; Hawkins, Clare Louise; Davies, Michael Jonathan.
In: Chemical Research in Toxicology, Vol. 16, No. 4, 04.2003, p. 439-49.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Hypochlorous acid-mediated oxidation of lipid components and antioxidants present in low-density lipoproteins
T2 - absolute rate constants, product analysis, and computational modeling
AU - Pattison, David I
AU - Hawkins, Clare Louise
AU - Davies, Michael Jonathan
PY - 2003/4
Y1 - 2003/4
N2 - Oxidation of low-density lipoproteins (LDL) is believed to contribute to the increased uptake of LDL by macrophages, which is an early event in atherosclerosis. Hypochlorous acid (HOCl) has been implicated as one of the major oxidants involved in these processes. In a previous study, the rates of reaction of HOCl with the reactive sites in proteins were investigated (Pattison, D. I., and Davies, M. J. (2001) Chem. Res. Toxicol. 14, 1453-1464). The work presented here expands on those studies to determine absolute second-order rate constants for the reactions of HOCl with various lipid components and antioxidants in aqueous solution (pH 7.4). The reactions of HOCl with phosphoryl-serine and phosphoryl-ethanolamine are rapid (k approximately 10(5) M(-)(1) s(-)(1)) and of comparable reactivity to many of the protein sites. The major products formed in these reactions are chloramines, which decay to give both nitrogen- and carbon-centered radicals. Subsequent reactions of these species may induce oxidation of the LDL lipid component. In contrast, phosphoryl-choline reacted much more slowly (k < 10(-)(2) M(-)(1) s(-)(1)). Reaction of HOCl with 3-pentenoic acid was used as a model of lipid double bonds and yielded k = 9 M(-)(1) s(-)(1). The reactions of the lipid-soluble antioxidants, alpha-tocopherol and ubiquinol-10, with HOCl were investigated with model compounds. For the reactions of HOCl with both Trolox and ubiquinol-0, k = 1.3 x 10(3) M(-)(1) s(-)(1); thus, these lipid soluble antioxidants are relatively ineffective as direct scavengers for HOCl as compared to water soluble antioxidants (e.g., ascorbate, k ca. 10(6) M(-)(1) s(-)(1)). The reaction of HOCl with hydroquinone (a simple model for ubiquinol-10) was also investigated both in aqueous solution (k = 45 M(-)(1) s(-)(1)) and in a less polar environment (k approximately 0.5 M(-)(1) s(-)(1) in THF). A computational model was developed using these kinetic parameters to predict which LDL targets are oxidized with varying molar excesses of HOCl, in both the absence and the presence of added ascorbate. The results from these models compare well with experimental data and can be used to predict the effects of HOCl-mediated oxidation on LDL composition.
AB - Oxidation of low-density lipoproteins (LDL) is believed to contribute to the increased uptake of LDL by macrophages, which is an early event in atherosclerosis. Hypochlorous acid (HOCl) has been implicated as one of the major oxidants involved in these processes. In a previous study, the rates of reaction of HOCl with the reactive sites in proteins were investigated (Pattison, D. I., and Davies, M. J. (2001) Chem. Res. Toxicol. 14, 1453-1464). The work presented here expands on those studies to determine absolute second-order rate constants for the reactions of HOCl with various lipid components and antioxidants in aqueous solution (pH 7.4). The reactions of HOCl with phosphoryl-serine and phosphoryl-ethanolamine are rapid (k approximately 10(5) M(-)(1) s(-)(1)) and of comparable reactivity to many of the protein sites. The major products formed in these reactions are chloramines, which decay to give both nitrogen- and carbon-centered radicals. Subsequent reactions of these species may induce oxidation of the LDL lipid component. In contrast, phosphoryl-choline reacted much more slowly (k < 10(-)(2) M(-)(1) s(-)(1)). Reaction of HOCl with 3-pentenoic acid was used as a model of lipid double bonds and yielded k = 9 M(-)(1) s(-)(1). The reactions of the lipid-soluble antioxidants, alpha-tocopherol and ubiquinol-10, with HOCl were investigated with model compounds. For the reactions of HOCl with both Trolox and ubiquinol-0, k = 1.3 x 10(3) M(-)(1) s(-)(1); thus, these lipid soluble antioxidants are relatively ineffective as direct scavengers for HOCl as compared to water soluble antioxidants (e.g., ascorbate, k ca. 10(6) M(-)(1) s(-)(1)). The reaction of HOCl with hydroquinone (a simple model for ubiquinol-10) was also investigated both in aqueous solution (k = 45 M(-)(1) s(-)(1)) and in a less polar environment (k approximately 0.5 M(-)(1) s(-)(1) in THF). A computational model was developed using these kinetic parameters to predict which LDL targets are oxidized with varying molar excesses of HOCl, in both the absence and the presence of added ascorbate. The results from these models compare well with experimental data and can be used to predict the effects of HOCl-mediated oxidation on LDL composition.
KW - Antioxidants
KW - Chloramines
KW - Computer Simulation
KW - Free Radicals
KW - Hypochlorous Acid
KW - Kinetics
KW - Lipids
KW - Oxidation-Reduction
KW - Phospholipids
U2 - 10.1021/tx025670s
DO - 10.1021/tx025670s
M3 - Journal article
C2 - 12703960
VL - 16
SP - 439
EP - 449
JO - Chemical Research in Toxicology
JF - Chemical Research in Toxicology
SN - 0893-228X
IS - 4
ER -
ID: 138276106