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Differential inhibition of human cytochrome P450 2A6 and 2B6 by major phytocannabinoids

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Abstract

Inhibitory effects of Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), and cannabinol (CBN) on the catalytic activities of human recombinant cytochrome P450 (CYP) 2A6 and CYP2B6 were investigated. Δ9-THC, CBD, and CBN noncompetitively inhibited coumarin 7-hydroxylase activity of recombinant CYP2A6 with the apparent K i values of 28.9, 55.0, and 39.8 μM, respectively. On the other hand, Δ9-THC, CBD, and CBN inhibited 7-benzoxyresorufin O-debenzylase activity of recombinant CYP2B6 in a mixed fashion with the K i values of 2.81, 0.694, and 2.55 μM, respectively. Because the inhibition of CYP2B6 by CBD was the most potent, investigation was conducted to determine which moiety of the CBD structure was responsible for the inhibition. Olivetol and d-limonene, the partial structure of CBD, inhibited the CYP2B6 activity to some extent. Inhibitory effects of CBD-2′-monomethyl ether and CBD-2′,6′-dimethyl ether attenuated with the number of methylations on the phenolic hydroxyl groups in the resorcinol moiety of CBD. Cannabidivarin, a CBD analogue having a propyl side chain, inhibited the CYP2B6 activity less potently than CBD possessing a pentyl side chain. Therefore, both structures of pentylresorcinol and terpene moieties of CBD were suggested to play important roles in the CYP2B6 inhibition. Δ9-THC, CBD, and CBN showed metabolism-dependent inhibition for CYP2A6 but not for CYP2B6. Furthermore, Δ9-THC and CBN were characterized as mechanism-based inhibitors for CYP2A6. The k inact and K I values of Δ9-THC were 0.0169 min−1 and 0.862 μM, respectively; the k inact and K I values of CBN were 0.00909 min−1 and 1.01 μM, respectively. These results indicated that Δ9-THC, CBD, and CBN showed differential inhibition against CYP2A6 and CYP2B6.

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Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research (C) and the ‘Academic Frontier’ Project for Private Universities (2005–2009) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The authors thank Dr. Yukihiro Shoyama (Faculty of Pharmaceutical Sciences, Nagasaki International University, Sasebo, Japan) for generously providing CBDV.

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Authors and Affiliations

  1. Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa-machi, Kanazawa, 920-1181, Japan

    Satoshi Yamaori, Chikako Maeda & Kazuhito Watanabe

  2. Organization for Frontier Research in Preventive Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan

    Kazuhito Watanabe

  3. Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, Nobeoka, Japan

    Ikuo Yamamoto

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  1. Satoshi Yamaori
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Correspondence to Kazuhito Watanabe.

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Yamaori, S., Maeda, C., Yamamoto, I. et al. Differential inhibition of human cytochrome P450 2A6 and 2B6 by major phytocannabinoids. Forensic Toxicol 29, 117–124 (2011). https://doi.org/10.1007/s11419-011-0112-7

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  • DOI: https://doi.org/10.1007/s11419-011-0112-7

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