title: Cannabidiol-2',6'-dimethyl ether as an effective protector of 15-lipoxygenase-mediated low-density lipoprotein oxidation in vitro.
abstract: 15-Lipoxygenase (15-LOX) is one of the key enzymes responsible for the formation of oxidized low-density lipoprotein (ox-LDL), a major causal factor for atherosclerosis. Both enzymatic (15-LOX) and non-enzymatic (Cu(2+)) mechanisms have been proposed for the production of ox-LDL. We have recently reported that cannabidiol-2',6'-dimethyl ether (CBDD) is a selective and potent inhibitor of 15-LOX-catalyzed linoleic acid oxygenation (Takeda et al., Drug Metab. Dispos., 37, 1733-1737 (2009)). In the LDL, linoleic acid is present as cholesteryl linoleate, the major fatty acid esterified to cholesterol, and is susceptible to oxidative modification by 15-LOX or Cu(2+). In this investigation, we examined the efficacy of CBDD on i) 15-LOX-catalyzed oxygenation of cholesteryl linoleate, and ii) ox-LDL formation catalyzed by 15-LOX versus Cu(2+)-mediated non-enzymatic generation of this important mediator. The results obtained demonstrate that CBDD is a potent and selective inhibitor of ox-LDL formation generated by the 15-LOX pathway. These studies establish CBDD as both an important experimental tool for characterizing 15-LOX-mediated ox-LDL formation, and as a potentially useful therapeutic agent for treatment of atherosclerosis.
authors.affiliation: Department of Molecular Biology, Daiichi University of Pharmacy, Fukuoka 815–8511, Japan.
authors.forename: Shuso
authors.initials: S
authors.lastname: Takeda
authors.forename: Akari
authors.initials: A
authors.lastname: Hirayama
authors.forename: Shino
authors.initials: S
authors.lastname: Urata
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Mano
authors.forename: Keiko
authors.initials: K
authors.lastname: Fukagawa
authors.forename: Midori
authors.initials: M
authors.lastname: Imamura
authors.forename: Ayumi
authors.initials: A
authors.lastname: Irii
authors.forename: Satomi
authors.initials: S
authors.lastname: Kitajima
authors.forename: Tomoko
authors.initials: T
authors.lastname: Masuyama
authors.forename: Mai
authors.initials: M
authors.lastname: Nomiyama
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tatei
authors.forename: Saari
authors.initials: S
authors.lastname: Tomita
authors.forename: Taichi
authors.initials: T
authors.lastname: Kudo
authors.forename: Momoko
authors.initials: M
authors.lastname: Noguchi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Amamoto
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Fukunishi
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Watanabe
authors.forename: Curtis John
authors.initials: CJ
authors.lastname: Omiecinski
authors.forename: Hironori
authors.initials: H
authors.lastname: Aramaki
mesh_terms: D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism; D002185:Cannabidiol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002788:Cholesterol Esters / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000096:biosynthesis*; D010084:Oxidation-Reduction
chemical_list: D000975:Antioxidants; D002788:Cholesterol Esters; D008078:Cholesterol, LDL; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; C065844:cannabidiol dimethyl ether; D002185:Cannabidiol; C021976:cholesteryl linoleate; D003300:Copper; D001093:Arachidonate 15-Lipoxygenase