Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: Role of phenolic hydroxyl groups in the resorcinol moiety
Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: Role of phenolic hydroxyl groups in the resorcinol moiety
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DOI：
10.1016/j.lfs.2011.02.017
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发表时间：
2011-04-11
期刊：
影响因子：
6.1
通讯作者：
Watanabe, Kazuhito
中科院分区：
文献类型：
--
作者：
Yamaori, Satoshi;Ebisawa, Juri;Watanabe, Kazuhito
目的：在本研究中，我们检测了三种主要大麻素 Delta(9)-四氢大麻酚 (Delta(9)-THC)、大麻二酚 (CBD) 和大麻酚 (CBN) 对人细胞色素 P450 (CYP) 3A 酶活性的抑制作用。此外，我们还研究了 CBD 对 CYP3A 活性抑制作用的动力学和结构要求。主要方法：测定了重组 CYP3A4、CYP3A5、CYP3A7 和人肝微粒体 (HLM) 在大麻素存在下的地尔硫卓 N-去甲基酶活性。主要发现：在三种主要大麻素中，CBD 最有效地抑制 CYP3A4 和CYP3A5（IC50分别=11.7和1.65μM）。 Delta(9)-THC和CBN对CYP3A4和CYP3A5的IC50值高于35μM。对于CYP3A7，Delta(9)-THC、CBD和CBN抑制活性达到相似程度(IC50=23-31μM)。 CBD 竞争性抑制 CYP3A4、CYP3A5 和 HLM 的活性（K-i 分别为 1.00、0.195 和 6.14 muM）。另一方面，CBD以混合方式抑制CYP3A7活性(K-i=12.3μM)。 Olivetol 部分抑制所有测试的 CYP3A 同工型，而 d-柠檬烯则缺乏抑制作用。 CBD的单甲醚和二甲醚的抑制作用较小，表明大麻素对CYP3A的抑制能力随着间苯二酚部分中酚羟基甲基化的数量而减弱。意义：本研究表明CBD最有效地抑制人类CYP3A酶的催化活性，特别是CYP3A4和CYP3A5。这些结果表明 CBD 间苯二酚部分中的两个酚羟基可能在 CYP3A 抑制中发挥重要作用。 (C) 2011 Elsevier Inc. 保留所有权利。
Aims: In this study, we examined the inhibitory effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), cannabidiol (CBD), and cannabinol (CBN), the three major cannabinoids, on the activity of human cytochrome P450 (CYP) 3A enzymes. Furthermore, we investigated the kinetics and structural requirement for the inhibitory effect of CBD on the CYP3A activity.Main methods: Diltiazem N-demethylase activity of recombinant CYP3A4, CYP3A5, CYP3A7, and human liver microsomes (HLMs) in the presence of cannabinoids was determined.Key findings: Among the three major cannabinoids, CBD most potently inhibited CYP3A4 and CYP3A5 (IC50=11.7 and 1.65 mu M, respectively). The IC50 values of Delta(9)-THC and CBN for CYP3A4 and CYP3A5 were higher than 35 mu M. For CYP3A7, Delta(9)-THC, CBD, and CBN inhibited the activity to a similar extent (IC50=23-31 mu M). CBD competitively inhibited the activity of CYP3A4, CYP3A5, and HLMs (K-i=1.00, 0.195, and 6.14 mu M, respectively). On the other hand, CBD inhibited the CYP3A7 activity in a mixed manner (K-i=12.3 mu M). Olivetol partially inhibited all the CYP3A isoforms tested, whereas d-limonene showed lack of inhibition. The lesser inhibitory effects of monomethyl and dimethyl ethers of CBD indicated that the ability of CYP3A inhibition by the cannabinoid attenuated with the number of methylation on the phenolic hydroxyl groups in the resorcinol moiety.Significance: This study indicated that CBD most potently inhibited catalytic activity of human CYP3A enzymes, especially CYP3A4 and CYP3A5. These results suggest that two phenolic hydroxyl groups in the resorcinol moiety of CBD may play an important role in the CYP3A inhibition. (C) 2011 Elsevier Inc. All rights reserved.