Transformation of berberine to its demethylated metabolites by the CYP51 enzyme in the gut microbiota.
Transformation of berberine to its demethylated metabolites by the CYP51 enzyme in the gut microbiota.
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肠道微生物群中 CYP51 酶将小檗碱转化为其去甲基化代谢物
DOI：
10.1016/j.jpha.2020.10.001
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发表时间：
2021-10
影响因子：
8.8
通讯作者：
Jiang JD
中科院分区：
文献类型：
--
作者：
Zhang ZW;Cong L;Peng R;Han P;Ma SR;Pan LB;Fu J;Yu H;Wang Y;Jiang JD
小檗碱（BBR）是从黄连中提取的异喹啉生物碱，可改善糖尿病、高脂血症和炎症。由于BBR的口服生物利用度低，其作用机制与肠道微生物群密切相关。本研究以肠道细菌的CYP51酶为研究对象，通过多种分析技术阐明肠道菌群中BBR通过去甲基化转化的新机制。首先进行了BBR与CYP51的对接，然后在ICR小鼠体内测定了BBR的药代动力学，并在体外检测了BBR在肝、肾、肠道菌群和单一菌株中的代谢。此外，ICR小鼠粪便的16S rRNA分析表明BBR与肠道微生物群之间的关系。最后，构建了含CYP 51基因的重组大肠杆菌，并诱导表达CYP 51酶裂解液。在CYP51酶裂解系统中分析了BBR的代谢特征。结果表明，肠道菌群中的CYP51能与BBR稳定结合，添加CYP51特异性抑制剂伏立康唑可减缓BBR的代谢，从而阻止脱甲基代谢产物噻苯芬定和小檗红宾的产生。本研究证明CYP51促进了BBR的去甲基化，增强了其肠道吸收，为研究异喹啉生物碱的体内代谢转化机制提供了新的方法。首次报道了难以通过肠道微生物群吸收的天然药物的脱甲基代谢。提出了六种不同的方法来解释天然异喹啉生物碱的代谢机制。这一发现为研究肠道菌群的药物代谢机制提供了新的思路。
Berberine (BBR) is an isoquinoline alkaloid extracted from Coptis chinensis that improves diabetes, hyperlipidemia and inflammation. Due to the low oral bioavailability of BBR, its mechanism of action is closely related to the gut microbiota. This study focused on the CYP51 enzyme of intestinal bacteria to elucidate a new mechanism of BBR transformation by demethylation in the gut microbiota through multiple analytical techniques. First, the docking of BBR and CYP51 was performed; then, the pharmacokinetics of BBR was determined in ICR mice in vivo, and the metabolism of BBR in the liver, kidney, gut microbiota and single bacterial strains was examined in vitro. Moreover, 16S rRNA analysis of ICR mouse feces indicated the relationship between BBR and the gut microbiota. Finally, recombinant E. coli containing cyp51 gene was constructed and the CYP51 enzyme lysate was induced to express. The metabolic characteristics of BBR were analyzed in the CYP51 enzyme lysate system. The results showed that CYP51 in the gut microbiota could bind stably with BBR, and the addition of voriconazole (a specific inhibitor of CYP51) slowed down the metabolism of BBR, which prevented the production of the demethylated metabolites thalifendine and berberrubine. This study demonstrated that CYP51 promoted the demethylation of BBR and enhanced its intestinal absorption, providing a new method for studying the metabolic transformation mechanism of isoquinoline alkaloids in vivo. The demethylation metabolism of natural drugs difficult to absorb through the gut microbiota was first reported. Six different methods were presented to explain the metabolic mechanism of natural isoquinoline alkaloids. The findings provided a new idea for studying the mechanism of drug metabolism of gut microbiota.
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影响因子：
7
作者：
Castellarin, Mauro;Warren, Rene L.;Holt, Robert A.
通讯作者：
Holt, Robert A.
DOI：
10.1073/pnas.0504978102
发表时间：
2005-08-02
影响因子：
11.1
作者：
Ley, RE;Bäckhed, F;Gordon, JI
通讯作者：
Gordon, JI
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影响因子：
64.8
作者：
Wang, Zeneng;Klipfell, Elizabeth;Bennett, Brian J.;Koeth, Robert;Levison, Bruce S.;Dugar, Brandon;Feldstein, Ariel E.;Britt, Earl B.;Fu, Xiaoming;Chung, Yoon-Mi;Wu, Yuping;Schauer, Phil;Smith, Jonathan D.;Allayee, Hooman;Tang, W. H. Wilson;DiDonato, Joseph A.;Lusis, Aldons J.;Hazen, Stanley L.
通讯作者：
Hazen, Stanley L.
枯草芽孢杆菌 MA139 发酵的日粮玉米麸减少育肥猪肠道纤维素分解细菌和微生物群多样性
影响因子：
5.7
作者：
Liu P;Zhao J;Guo P;Lu W;Geng Z;Levesque CL;Johnston LJ;Wang C;Liu L;Zhang J;Ma N;Qiao S;Ma X
通讯作者：
Ma X
DOI：
10.1038/nrgastro.2010.117
发表时间：
2010-09
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
Gareau MG;Sherman PM;Walker WA
通讯作者：
Walker WA