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Research ArticleArticle

Cannabidiolic Acid as a Selective Cyclooxygenase-2 Inhibitory Component in Cannabis

Shuso Takeda, Koichiro Misawa, Ikuo Yamamoto and Kazuhito Watanabe
Drug Metabolism and Disposition September 2008, 36 (9) 1917-1921; DOI: https://doi.org/10.1124/dmd.108.020909
Shuso Takeda
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Koichiro Misawa
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Ikuo Yamamoto
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Kazuhito Watanabe
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Abstract

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.

Footnotes

  • This study was supported in part by a Grant-in-Aid for Scientific Research (C) (Research No. 20590127, recipient K.W.) and by a Grant-in-Aid for Young Scientists (B) (Research No. 20790149, recipient S.T.) from the Ministry of Education, Culture, Sport, Science, and Technology of Japan. This study was also supported by the Academic Frontier Project for Private Universities from the Ministry of Education, Culture, Sport, Science, and Technology of Japan.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.020909.

  • ABBREVIATIONS: Δ9-THC, Δ9-tetrahydrocannabinol; CBD, cannabidiol; Δ9-THCA, Δ9-tetrahydrocannabinolic acid; CBDA, cannabidiolic acid; COX, cyclooxygenase; PG, prostaglandin; AA, arachidonic acid; NSAID, nonsteroidal anti-inflammatory drug; GC, gas chromatography; TMPD, N,N,N′,N′-tetramethyl-p-phenylenediamine.

    • Received February 7, 2008.
    • Accepted June 10, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (9)
Drug Metabolism and Disposition
Vol. 36, Issue 9
1 Sep 2008
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Research ArticleArticle

Cannabidiolic Acid as a Selective Cyclooxygenase-2 Inhibitory Component in Cannabis

Shuso Takeda, Koichiro Misawa, Ikuo Yamamoto and Kazuhito Watanabe
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1917-1921; DOI: https://doi.org/10.1124/dmd.108.020909

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Research ArticleArticle

Cannabidiolic Acid as a Selective Cyclooxygenase-2 Inhibitory Component in Cannabis

Shuso Takeda, Koichiro Misawa, Ikuo Yamamoto and Kazuhito Watanabe
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1917-1921; DOI: https://doi.org/10.1124/dmd.108.020909
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