Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
Drug Metab Pharmacokinet. 2013;28(4):332-8. doi: 10.2133/dmpk.dmpk-12-rg-129. Epub 2013 Jan 15.
The present study investigated the inhibitory effect of cannabidiol (CBD), a major constituent of marijuana, on the catalytic activity of cytochrome P450 2C19 (CYP2C19). (S)-Mephenytoin 4'-hydroxylase activities of human liver microsomes (HLMs) and recombinant CYP2C19 were inhibited by CBD in a concentration-dependent manner (IC₅₀ = 8.70 and 2.51 µM, respectively). Omeprazole 5-hydroxylase and 3-O-methylfluorescein O-demethylase activities in recombinant CYP2C19 were also strongly inhibited by CBD (IC₅₀ = 1.55 and 1.79 µM, respectively). Kinetic analysis for inhibition revealed that CBD showed a mixed-type inhibition against (S)-mephenytoin 4'-hydroxylation by recombinant CYP2C19. To clarify the structural requirements for CBD-mediated CYP2C19 inhibition, the effects of CBD-related compounds on CYP2C19 activity were examined. Olivetol inhibited the (S)-mephenytoin 4'-hydroxylase activity of recombinant CYP2C19 with the IC₅₀ value of 15.3 µM, whereas d-limonene slightly inhibited the activity (IC₅₀ > 50 µM). The inhibitory effect of CBD-2'-monomethyl ether (IC₅₀ = 1.88 µM) on CYP2C19 was comparable to that of CBD, although the inhibitory potency of CBD-2',6'-dimethyl ether (IC₅₀ = 14.8 µM) was lower than that of CBD. Cannabidivarin, possessing a propyl side chain, showed slightly less potent inhibition (IC₅₀ = 3.45 µM) as compared with CBD, whereas orcinol and resorcinol did not inhibit CYP2C19 activity at all. These results indicate that CBD caused potent CYP2C19 inhibition, in which one free phenolic hydroxyl group and the pentyl side chain of CBD may play important roles.
本研究探讨了大麻主要成分大麻二酚（CBD）对细胞色素 P450 2C19（CYP2C19）催化活性的抑制作用。（S）-美芬妥因 4'-羟化酶活性的人肝微粒体（HLMs）和重组 CYP2C19 被 CBD 浓度依赖性抑制（IC₅₀值分别为 8.70 和 2.51 μM）。奥美拉唑 5-羟化酶和 3-O-甲基荧光素 O-脱甲基酶活性在重组 CYP2C19 中也被 CBD 强烈抑制（IC₅₀值分别为 1.55 和 1.79 μM）。抑制的动力学分析表明，CBD 对重组 CYP2C19 的（S）-美芬妥因 4'-羟化表现出混合抑制作用。为了阐明 CBD 介导的 CYP2C19 抑制的结构要求，研究了 CBD 相关化合物对 CYP2C19 活性的影响。橄榄醇抑制重组 CYP2C19 的（S）-美芬妥因 4'-羟化酶活性，IC₅₀值为 15.3 μM，而柠檬烯则轻微抑制活性（IC₅₀值大于 50 μM）。CBD-2'-单甲基醚（IC₅₀= 1.88 μM）对 CYP2C19 的抑制作用与 CBD 相当，尽管 CBD-2'，6'-二甲醚（IC₅₀= 14.8 μM）的抑制作用低于 CBD。具有丙基侧链的大麻二酚具有稍低的抑制能力（IC₅₀= 3.45 μM），与 CBD 相比，而间苯二酚和间苯三酚则根本不抑制 CYP2C19 活性。这些结果表明，CBD 导致了强烈的 CYP2C19 抑制作用，其中 CBD 的一个游离酚羟基和戊基侧链可能起重要作用。
