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首页> 外文期刊>Life sciences >Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety.
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Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety.

机译：大麻二酚对人细胞色素P450 3A亚型的有效抑制：间苯二酚部分中酚羟基的作用。

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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 (IC(50)=11.7 and 1.65 muM, respectively). The IC(50) values of Delta(9)-THC and CBN for CYP3A4 and CYP3A5 were higher than 35 muM. For CYP3A7, Delta(9)-THC, CBD, and CBN inhibited the activity to a similar extent (IC(50)=23-31 muM). CBD competitively inhibited the activity of CYP3A4, CYP3A5, and HLMs (K(i)=1.00, 0.195, and 6.14 muM, respectively). On the other hand, CBD inhibited the CYP3A7 activity in a mixed manner (K(i)=12.3 muM). 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.
机译：目的：在这项研究中，我们研究了Delta（9）-四氢大麻酚（Delta（9）-THC），大麻酚（CBD）和大麻酚（CBN）这三种主要大麻素对人细胞色素P450活性的抑制作用（CYP）3A酶。此外，我们研究了CBD对CYP3A活性抑制作用的动力学和结构要求。主要方法：在存在大麻素的情况下，测定了重组CYP3A4，CYP3A5，CYP3A7和人肝微粒体（HLM）的地尔硫卓N-脱甲基酶活性。主要发现：在三种主要大麻素中，CBD最有效地抑制了CYP3A4和CYP3A5（分别为IC（50）= 11.7和1.65μM）。 CYP3A4和CYP3A5的Delta（9）-THC和CBN的IC（50）值高于35μM。对于CYP3A7，Delta（9）-THC，CBD和CBN抑制活性的程度相似（IC（50）= 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6.14μM）。另一方面，CBD以混合方式（K（i）＝12.3μM）抑制CYP3A7活性。 Olivetol部分抑制所有测试的CYP3A亚型，而d-柠檬烯缺乏抑制作用。 CBD的单甲基醚和二甲基醚的抑制作用较小，这表明大麻酚对CYP3A的抑制作用随间苯二酚部分中酚羟基的甲基化数目而减弱。意义：这项研究表明，CBD最有效地抑制了人CYP3A酶的催化活性，尤其是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抑制中起重要作用。

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