title: Gemfibrozil metabolite inhibits in vitro low-density lipoprotein (LDL) oxidation and diminishes cytotoxicity induced by oxidized LDL.
abstract: We hypothesized that M1, a metabolite of gemfibrozil, may have antioxidant properties because of its hydroxylated phenol ring, 5-(4-hydroxy-2,5-dimethyl-phenoxy)-2,2-dimethyl pentanoic acid. The susceptibility of low-density lipoprotein (LDL) to oxidative modification was investigated by a method using 2,2-azobis(4-methoxy-2,4-dimethylvaleronitrile [MeO-AMVN]) or Cu2+ as previously reported. Conjugated dienes (CDs), lipid hydroperoxide (LPO), and thiobarbituric acid-reactive substances (TBARS) were measured to evaluate the degree of LDL oxidation. Oxidized LDL (OxLDL), which is used for cytotoxicity studies, was prepared by the dialysis method using Cu2+ as the oxidation inducer. Cytotoxicity induced by OxLDL was studied in J774 macrophages by colorimetric assay using 3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT assay). The oxidative modification of LDL was inhibited by M1 in a dose-dependent manner. The antioxidant effect of M1 on LDL oxidation was diminished by dialysis of the LDL incubated with M1 against phosphate-buffered saline (PBS), suggesting that M1 is hydrophilic rather than lipophilic. M1 diminished the cytotoxicity induced by OxLDL, although it was milder versus probucol. These data suggest that this gemfibrozil metabolite has an antioxidant effect on LDL, and thus M1 may contribute to the antiatherogenic effects of gemfibrozil.
authors.affiliation: Department of Internal Medicine, Tokyo Teishin Hospital, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kawamura
authors.forename: S
authors.initials: S
authors.lastname: Miyazaki
authors.forename: T
authors.initials: T
authors.lastname: Teramoto
authors.forename: K
authors.initials: K
authors.lastname: Ashidate
authors.forename: H
authors.initials: H
authors.lastname: Thoda
authors.forename: N
authors.initials: N
authors.lastname: Ando
authors.forename: K
authors.initials: K
authors.lastname: Kaneko
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D001391:Azo Compounds / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000494:pharmacology; D015248:Gemfibrozil / Q000378:metabolism*; D006801:Humans; D000960:Hypolipidemic Agents / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology*; D008264:Macrophages / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010421:Pentanoic Acids / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology*; D011341:Probucol / Q000494:pharmacology
chemical_list: C407182:5-(4-hydroxy-2,5-dimethylphenoxy)-2,2-dimethyl pentanoic acid; D000975:Antioxidants; D001391:Azo Compounds; D000960:Hypolipidemic Agents; D008077:Lipoproteins, LDL; D009570:Nitriles; D010421:Pentanoic Acids; D010636:Phenols; C099252:oxidized low density lipoprotein; C109522:V 70; D003300:Copper; D011341:Probucol; D015248:Gemfibrozil