RT Journal Article
SR Electronic
T1 Cannabidiolic Acid as a Selective Cyclooxygenase-2 Inhibitory Component in Cannabis
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1917
OP 1921
DO 10.1124/dmd.108.020909
VO 36
IS 9
A1 Shuso Takeda
A1 Koichiro Misawa
A1 Ikuo Yamamoto
A1 Kazuhito Watanabe
YR 2008
UL http://dmd.aspetjournals.org/content/36/9/1917.abstract
AB In the present study it was revealed that cannabidiolic acid (CBDA) selectively inhibited cyclooxygenase (COX)-2 activity with an IC50 value (50% inhibition concentration) around 2 μM, having 9-fold higher selectivity than COX-1 inhibition. In contrast, Δ9-tetrahydrocannabinolic acid (Δ9-THCA) was a much less potent inhibitor of COX-2 (IC50 > 100 μM). Nonsteroidal anti-inflammatory drugs containing a carboxyl group in their chemical structures such as salicylic acid are known to inhibit nonselectively both COX-1 and COX-2. CBDA and Δ9-THCA have a salicylic acid moiety in their structures. Thus, the structural requirements for the CBDA-mediated COX-2 inhibition were next studied. There is a structural difference between CBDA and Δ9-THCA; phenolic hydroxyl groups of CBDA are freed from the ring formation with the terpene moiety, although Δ9-THCA has dibenzopyran ring structure. It was assumed that the whole structure of CBDA is important for COX-2 selective inhibition because β-resorcylic acid itself did not inhibit COX-2 activity. Methylation of the carboxylic acid moiety of CBDA led to disappearance of COX-2 selectivity. Thus, it was suggested that the carboxylic acid moiety in CBDA is a key determinant for the inhibition. Furthermore, the crude extract of cannabis containing mainly CBDA was shown to have a selective inhibitory effect on COX-2. Taken together, these lines of evidence in this study suggest that naturally occurring CBDA in cannabis is a selective inhibitor for COX-2. The American Society for Pharmacology and Experimental Therapeutics