title: Atorvastatin active metabolite inhibits oxidative modification of small dense low-density lipoprotein.
abstract: We tested the hypothesis that atorvastatin active metabolite (ATM), on the basis of its distinct structural features and potent antioxidant activity, preferentially inhibits lipid oxidation in human small dense low-density lipoprotein (sdLDL) and other small lipid vesicles. LDL, sdLDL, and various subfractions were isolated from human plasma by sequential ultracentrifugation, treated with ATM, atorvastatin, pravastatin, rosuvastatin, or simvastatin and were subjected to copper-induced oxidation. Lipid oxidation was measured spectrophotometrically as a function of thiobarbituric acid reactive substances formation. Similar analyses were performed in reconstituted lipid vesicles enriched in polyunsaturated fatty acids and prepared at various sizes. ATM was found to inhibit sdLDL oxidation in a dose-dependent manner. The antioxidant effects of ATM in sdLDL were 1.5 and 4.7 times greater (P < 0.001) than those observed in large buoyant LDL and very low-density lipoprotein subfractions, respectively. ATM had similar dose- and size-dependent effects in reconstituted lipid vesicles. None of these effects were reproduced by atorvastatin (parent) or any of the other statins examined in this study. These data suggest that ATM interacts with sdLDL in a specific manner that also confers preferential resistance to oxidative stress. Such interactions may reduce sdLDL atherogenicity and improve clinical outcomes in patients with cardiovascular disease.
authors.affiliation: Elucida Research LLC, Beverly, MA 01915, USA. cob@elucidaresearch.com
authors.forename: Robert F
authors.initials: RF
authors.lastname: Jacob
authors.forename: Mary F
authors.initials: MF
authors.lastname: Walter
authors.forename: Yehudi
authors.initials: Y
authors.lastname: Self-Medlin
authors.forename: R Preston
authors.initials: RP
authors.lastname: Mason
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D000069059:Atorvastatin / Q000031:analogs & derivatives; D055598:Chemical Phenomena; D019327:Copper Sulfate / Q000009:adverse effects / Q000037:antagonists & inhibitors; D006538:Heptanoic Acids / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008054:Lipid Peroxides / Q000032:analysis / Q000037:antagonists & inhibitors; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000302:isolation & purification; D008079:Lipoproteins, VLDL / Q000737:chemistry / Q000302:isolation & purification; D008081:Liposomes / Q000737:chemistry; D009994:Osmolar Concentration; D016877:Oxidants / Q000009:adverse effects / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010316:Particle Size; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology*; D014461:Ultracentrifugation; D053835:Unilamellar Liposomes / Q000737:chemistry
chemical_list: C518963:2-hydroxyatorvastatin; D000975:Antioxidants; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008054:Lipid Peroxides; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D008081:Liposomes; D016877:Oxidants; D011355:Prodrugs; D011758:Pyrroles; D053835:Unilamellar Liposomes; C099252:oxidized low density lipoprotein; D000069059:Atorvastatin; D019327:Copper Sulfate