Cytochrome P450-Catalyzed Metabolism of Cannabidiol to the Active Metabolite 7-Hydroxy-Cannabidiol
Cytochrome P450-Catalyzed Metabolism of Cannabidiol to the Active Metabolite 7-Hydroxy-Cannabidiol
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DOI：
10.1124/dmd.120.000350
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发表时间：
2021-10-01
影响因子：
3.9
通讯作者：
Jackson, Klarissa D.
中科院分区：
文献类型：
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作者：
Beers, Jessica L.;Fu, Dong;Jackson, Klarissa D.
大麻二酚（CBD）是一种天然存在的非精神毒性植物大麻素，作为一种受欢迎的消费品及其在食品和药物管理局批准的Epidiolex（CBD口服溶液）中用于治疗Lennox-Gastaut综合征和Dravet综合征而受到越来越多的关注。CBD以前被报道主要由CYP 2C 19和CYP 3A 4代谢，UDP-葡萄糖醛酸转移酶的贡献很小。7-羟基-CBD（7-OH-CBD）是CBD的主要活性代谢物，与CBD相比具有等效活性。鉴于CYP 2C 19的多态性，我们假设CYP 2C 19的表达变化可能导致CBD代谢为7-OH-CBD的个体间差异。本研究的目的是进一步表征细胞色素P450酶在CBD代谢中的作用，特别是活性代谢物7-OH-CBD，并研究CYP 2C 19多态性对基因型人肝微粒体中CBD代谢的影响。用重组细胞色素P450酶和细胞色素P450选择性化学抑制剂进行的反应表型实验的结果表明，CYP 2C 19和CYP 2C 9都能够将CBD代谢为7-OH-CBD。CYP 3A通过在7位以外的位点氧化在CBD代谢清除中起主要作用。在基因分型的人肝微粒体中，7-OH-CBD的形成与CYP 2C 19活性呈正相关，但与CYP 2C 19基因型无关。在具有中至低CYP 2C 19活性的单供体人肝微粒体亚组中，CYP 2C 9抑制显著减少7-OH-CBD形成，表明CYP 2C 9可能在CBD 7-羟基化中发挥比以前认为的更大的作用。总的来说，这些数据表明，CYP 2C 19和CYP 2C 9都是CBD代谢为活性代谢物7-OH-CBD的重要贡献者。重要性声明本研究表明，CYP 2C 19和CYP 2C 9都参与CBD代谢为活性代谢物7-OH-CBD，CYP 3A 4是CBD通过7-羟基化以外的途径代谢的主要贡献者。7-OH-CBD的形成与人肝微粒体CYP 2C 19活性有关，但与CYP 2C 19基因型无关，CYP 2C 9对7-OH-CBD的产生有显著贡献。这些发现对服用CBD的患者具有影响，这些患者可能存在临床上重要的细胞色素P450介导的药物相互作用的风险。
Cannabidiol (CBD) is a naturally occurring nonpsychotoxic phytocannabinoid that has gained increasing attention as a popular consumer product and for its use in Food and Drug Administration-approved Epidiolex (CBD oral solution) for the treatment of Lennox-Gastaut syndrome and Dravet syndrome. CBD was previously reported to be metabolized primarily by CYP2C19 and CYP3A4, with minor contributions from UDP-glucuronosyltransferases. 7-Hydroxy-CBD (7-OH-CBD) is the primary active metabolite with equipotent activity compared with CBD. Given the polymorphic nature of CYP2C19, we hypothesized that variable CYP2C19 expression may lead to interindividual differences in CBD metabolism to 7-OH-CBD. The objectives of this study were to further characterize the roles of cytochrome P450 enzymes in CBD metabolism, specifically to the active metabolite 7-OH-CBD, and to investigate the impact of CYP2C19 polymorphism on CBD metabolism in genotyped human liver microsomes. The results from reaction phenotyping experiments with recombinant cytochrome P450 enzymes and cytochrome P450-selective chemical inhibitors indicated that both CYP2C19 and CYP2C9 are capable of CBD metabolism to 7-OH-CBD. CYP3A played a major role in CBD metabolic clearance via oxidation at sites other than the 7-position. In genotyped human liver microsomes, 7-OH-CBD formation was positively correlated with CYP2C19 activity but was not associated with CYP2C19 genotype. In a subset of single-donor human liver microsomes with moderate to low CYP2C19 activity, CYP2C9 inhibition significantly reduced 7-OH-CBD formation, suggesting that CYP2C9 may play a greater role in CBD 7-hydroxylation than previously thought. Collectively, these data indicate that both CYP2C19 and CYP2C9 are important contributors in CBD metabolism to the active metabolite 7-OH-CBD.SIGNIFICANCE STATEMENTThis study demonstrates that both CYP2C19 and CYP2C9 are involved in CBD metabolism to the active metabolite 7-OH-CBD and that CYP3A4 is a major contributor to CBD metabolism through pathways other than 7-hydroxylation. 7-OH-CBD formation was associated with human liver microsomal CYP2C19 activity, but not CYP2C19 genotype, and CYP2C9 was found to contribute significantly to 7-OH-CBD generation. These findings have implications for patients taking CBD who may be at risk for clinically important cytochrome P450-mediated drug interactions.