Metabolites of Cannabigerol Generated by Human Cytochrome P450s Are Bioactive.
Metabolites of Cannabigerol Generated by Human Cytochrome P450s Are Bioactive.
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人细胞色素P450产生的大麻醇的代谢产物是生物活性的。
DOI：
10.1021/acs.biochem.2c00383
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发表时间：
2022-11-01
期刊：
影响因子：
2.9
通讯作者：
Das, Aditi
中科院分区：
文献类型：
--
作者：
Roy, Pritam;Dennis, David G.;Eschbach, Mark D.;Anand, Shravanthi D.;Xu, Fengyun;Maturano, Jonathan;Hellman, Judith;Sarlah, David;Das, Aditi
植物大麻素大麻酚（CBG）是许多大麻素的主要生物合成前体，包括Δ9-四氢大麻酚（THC）和大麻二酚（CBD）。尽管由于 CBG 对健康有益且缺乏精神活性，CBG 的使用最近出现了广泛的激增，但其通过人类细胞色素 P450 的代谢在很大程度上尚不清楚。在此，我们描述了全面的体外和体内细胞色素 P450 (CYP) 介导的 CBG 代谢研究，包括基于 LC-MS/MS 的主要代谢位点测定、合成验证和使用靶向质谱的动力学行为。这些研究表明，环 CBG 是一种最近分离的植物大麻素，是由选定的人类细胞色素 P450（CYP2J2、CYP3A4、CYP2D6、CYP2C8 和 CYP2C9）快速形成的主要代谢物。此外，对给予 CBG 的小鼠进行的体内研究支持了这些研究，其中环 CBG 也是主要代谢物。光谱结合研究以及 P450 活性位点血红素附近的 CBG 分子对接和建模证实了这些观察结果，表明 CBG 代谢在异戊二烯链上比其他位置具有优选的位点选择性。重要的是，我们发现 CBG 及其氧化 CBG 代谢物可减少 LPS 刺激的 BV2 小胶质细胞的炎症。总的来说，结合酶学研究、质谱分析和化学合成，我们展示了 CBG 被人类 P450 快速代谢，形成具有生物活性的氧化代谢物。该研究揭示了 CBG 代谢物和类似物与其抗炎活性的结构-活性关系。
The phytocannabinoid cannabigerol (CBG) is the central biosynthetic precursor to many cannabinoids, including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Though the use of CBG has recently witnessed a widespread surge because of its beneficial health effects and lack of psychoactivity, its metabolism by human cytochrome P450s is largely unknown. Herein, we describe comprehensive in vitro and in vivo cytochrome P450 (CYP)-mediated metabolic studies of CBG, ranging from LC-MS/MS-based primary metabolic site determination, synthetic validation, and kinetic behavior using targeted mass spectrometry. These investigations revealed that cyclo-CBG, a recently isolated phytocannabinoid, is the major metabolite that is rapidly formed by selected human cytochrome P450s (CYP2J2, CYP3A4, CYP2D6, CYP2C8, and CYP2C9). Additionally, in vivo studies with mice administered with CBG, supported these studies, where cyclo-CBG is the major metabolite as well. Spectroscopic binding studies along with docking and modeling of CBG molecule near the heme in the active site of P450s confirmed these observations, pointing at the preferred site-selectivity of CBG metabolism at the prenyl chain over other positions. Importantly, we found out that CBG and its oxidized CBG metabolites reduced inflammation in BV2 microglial cells stimulated with LPS. Overall, combining enzymological studies, mass spectrometry, and chemical synthesis, we showcase that CBG is rapidly metabolized by human P450s to form oxidized metabolites that are bioactive. The study reveals the structure-activity relationship of CBG metabolites and analogs to their anti-inflammatory activity.
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影响因子：
2.9
作者：
Denisov IG;Grinkova YV;Camp T;McLean MA;Sligar SG
通讯作者：
Sligar SG
DOI：
10.1002/bms.1200070107
发表时间：
1980-01-01
期刊：
BIOMEDICAL MASS SPECTROMETRY
影响因子：
--
作者：
HARVEY, DJ
通讯作者：
HARVEY, DJ
影响因子：
3.9
作者：
DeLozier, Tracy C.;Kissling, Grace E.;Goldstein, Joyce A.
通讯作者：
Goldstein, Joyce A.
影响因子：
5.6
作者：
Gugliandolo, Agnese;Pollastro, Federica;Mazzon, Emanuela
通讯作者：
Mazzon, Emanuela
影响因子：
3.4
作者：
Deiana, Serena;Watanabe, Akihito;Riedel, Gernot
通讯作者：
Riedel, Gernot