Journal
BIOLOGICAL & PHARMACEUTICAL BULLETIN
Volume 34, Issue 8, Pages 1252-1256Publisher
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/bpb.34.1252
Keywords
cannabidiol-2 ',6 '-dimethyl ether; 15-lipoxygenase; low-density lipoprotein; atherosclerosis; cannabinoid
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [20790149, 22790176]
- NEUES Corporation, Japan
- USPHS [ES016358]
- Grants-in-Aid for Scientific Research [20790149, 22790176] Funding Source: KAKEN
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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 (Cu2+) 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 Cu2+. 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 Cu2+-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.
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