Potent inhibitory activities of hydrophobic aci-reductones (2-hydroxytetronic acid analogs) against membrane and human low-density lipoprotein oxidation.
The effects of selected aci-reductones, which are hydrophobic ascorbate-related analogs including 4-chlorophenyl-2-hydroxytetronic acid (Cpd A), 4-(1,1'-biphenyl)-2-hydroxytetronic acid (Cpd B), and 4-(4'-chloro-1,1'-biphenyl)-2-hydroxytetronic acid (Cpd C), on membrane and low density lipoprotein (LDL) oxidation were assessed. Hepatic microsomal lipid peroxidation was induced by the ascorbate + Fe(II) chemical system. All three agents inhibited membrane lipid peroxidation in a concentration-dependent manner with the order of potency: Trolox (vitamin E) < or = Cpd A << Cpd B < Cpd C; based on the EC50 values, Cpd B and Cpd C were 11- and 19-fold, respectively, more potent than Trolox. In contrast to ascorbic acid, all three agents did not display any membrane prooxidative effect in the presence of iron. When human LDL was incubated with 10 microM of Cu(II), LDL oxidation, determined by the formation of thiobarbituric acid reactive substances, followed a typical sigmoidal curve with an initial lag phase. Preincubation of the LDL samples with low micromolar concentrations (1 and 3 microM) of each agents for 30 min before the addition of copper resulted in significant delays of the lag time of LDL oxidation, and the effectiveness of Cpd B and Cpd C was more prominent than that mediated by either Trolox or probucol. Since clinical evidence strongly supports the hypothesis that atherogenesis is initiated by LDL oxidation, the results suggest that these aryl tetronic acid analogs may serve as promising candidates for future therapeutic use as anti-atherogenic agents.
Department of Physiology and Experimental Medicine, George Washington University Medical Center, Washington, DC 20037, USA.
I T
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Mak
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Murphy
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Hopper
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Witiak
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Ziemniak
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Weglicki
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008563:Membrane Lipids / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
C113935:4-(1,1'-biphenyl)-2-hydroxytetronic acid; C113938:4-(4'-chloro-1,1'-biphenyl)-2-hydroxytetronic acid; D001713:Biphenyl Compounds; D005663:Furans; D000960:Hypolipidemic Agents; D008077:Lipoproteins, LDL; D008563:Membrane Lipids; C060438:4-(4-chlorophenyl)-2-hydroxytetronic acid