Abstract
The inhibitory effect of nordihydroguaiaretic acid (NDGA) (a nonselective lipoxygenase (LOX) inhibitor)-mediated 15-LOX inhibition has been reported to be affected by modification of its catechol ring, such as methylation of the hydroxyl group. Cannabidiol (CBD), one of the major components of marijuana, is known to inhibit LOX activity. Based on the phenomenon observed in NDGA, we investigated whether or not methylation of CBD affects its inhibitory potential against 15-LOX, because CBD contains a resorcinol ring, which is an isomer of catechol. Although CBD inhibited 15-LOX activity with an IC50 value (50% inhibition concentration) of 2.56 μM, its monomethylated and dimethylated derivatives, CBD-2′-monomethyl ether and CBD-2′,6′-dimethyl ether (CBDD), inhibited 15-LOX activity more strongly than CBD. The number of methyl groups in the resorcinol moiety of CBD (as a prototype) appears to be a key determinant for potency and selectivity in inhibition of 15-LOX. The IC50 value of 15-LOX inhibition by CBDD is 0.28 μM, and the inhibition selectivity for 15-LOX (i.e., the 5-LOX/15-LOX ratio of IC50 values) is more than 700. Among LOX isoforms, 15-LOX is known to be able to oxygenate cholesterol esters in the low-density lipoprotein (LDL) particle (i.e., the formation of oxidized LDL). Thus, 15-LOX is suggested to be involved in development of atherosclerosis, and CBDD may be a useful prototype for producing medicines for atherosclerosis.
Footnotes
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This study was supported in part by the Ministry of Education, Culture, Sport, Science and Technology of Japan [Grant-in-Aid for Scientific Research (C) 20590127 (to K.W.) and Grant-in-Aid for Young Scientists (B) 20790149 (to S.T.)]; and the Academic Frontier Project for Private Universities, Ministry of Education, Culture, Sport, Science and Technology of Japan.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.109.026930.
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ABBREVIATIONS: CBD, cannabidiol; LOX, lipoxygenase; NDGA, nordihydroguaiaretic acid; LDL, low-density lipoprotein; CBDM, CBD-2′-mono methyl ether; CBDD, CBD-2′,6′-dimehyl ether; THC, Δ9-tetrahydrocannabinol; CBN, cannabinol; CBDA, cannabidiolic acid; CBE, cannabielsoin; CBEM, monomethyl ether; CBDHQ, CBD-hydroxyquinone; AA-861, 2-(12-hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-1,4-benzoquinone.
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↵1 Current affiliation: Department of Molecular Biology, Daiichi University, College of Pharmaceutical Sciences, Fukuoka, Japan.
- Accepted April 27, 2009.
- Received January 26, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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