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Radical-Initiated Lipid Peroxidation in Low Density Lipoproteins: Insights Obtained from Kinetic Modeling

Waldeck, A. Reginald and Stocker, Roland (1996) Radical-Initiated Lipid Peroxidation in Low Density Lipoproteins: Insights Obtained from Kinetic Modeling. Chemical Research in Toxicology, 9 (6). pp. 954-964. ISSN 0893-228X. http://resolver.caltech.edu/CaltechAUTHORS:20180511-134521211

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Abstract

We present kinetic models of various complexity for radical-initiated lipid peroxidation in low density lipoproteins (LDL). The models, comprised of simultaneous differential equations programmed in Mathematica, were used to evaluate the concentration profiles of the reactants of interest. Single-phase reaction schemes describing lipid peroxidation and antioxidation according to the “conventional” and tocopherol-mediated peroxidation (TMP) model were simulated for conditions of low and high radical fluxes produced by thermolabile azo initiators. The results show that the particular dependencies of the rates of lipid peroxidation (R_p) on the rates of initiation (R_i) for the two reaction schemes were accurately predicted by the simulations. Both models qualitatively predicted inhibition of lipid peroxidation in the presence of α-tocopherol (α-TOH) under high radical flux conditions, suggesting that both can describe inhibited lipid peroxidation in solution under these conditions. TMP, but not the conventional model, could also predict the experimentally observed complex behavior of LDL lipid peroxidation induced with different concentrations of azo initiators. Specifically, TMP faithfully reproduced the observed kinetic chain length of lipid peroxidation of » 1 at low and « 1 at high concentration of the initiator (i.e., 0.2 and 10 mM, respectively for LDL at 1 µmol apoB-100/L) during the α-TOH-containing period of oxidation. It also demonstrated the experimentally observed nondependence of R_p^(TMP) on R_i. Kinetic analysis of radical generation and initiation of lipid peroxidation in an extended, two-compartment model of TMP showed that phase separation of bimolecular reactions in a suspension of LDL particles can lead to a �~400-fold increase in the rate of lipid hydroperoxide formation. The experimentally observed coantioxidant action of water-soluble ascorbate and lipid-soluble ubiquinol-10 were verified using this model. A simple biophysical model constituting the reactions of TMP and incorporating the compartmental nature of an LDL suspension is proposed. Together, the results demonstrate that TMP is the only model that fits the experimental data describing the early stages of LDL lipid peroxidation under various oxidizing conditions. The implications of our findings are discussed in relation to atherogenesis and a recently proposed alternative model of LDL lipid peroxidation (Abuja and Esterbauer (1995) Chem. Res. Toxicol. 8, 753).


Item Type:Article
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https://dx.doi.org/10.1021/tx960057sDOIArticle
https://pubs.acs.org/doi/suppl/10.1021/tx960057sPublisherSupporting Information
Additional Information:© 1996 American Chemical Society. Received March 28, 1996. We thank Dr. P. W. Kuchel for use of the computer facilities in his laboratory and valuable discussions, and Dr. H. Esterbauer for supplying us with a preprint of ref 28. This work received support from National Health and Medical Research Grant 940915 to R.S.
Funders:
Funding AgencyGrant Number
National Health and Medical Research Council (NHMRC)940915
Record Number:CaltechAUTHORS:20180511-134521211
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20180511-134521211
Official Citation:Radical-Initiated Lipid Peroxidation in Low Density Lipoproteins:  Insights Obtained from Kinetic Modeling A. Reginald Waldeck and Roland Stocker Chemical Research in Toxicology 1996 9 (6), 954-964 DOI: 10.1021/tx960057s
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:86367
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:14 May 2018 15:17
Last Modified:14 May 2018 15:17

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