Identification of naturally occurring inhibitors in Xian-Ling-Gu-Bao capsule against the glucuronidation of estrogens
文献类型：期刊论文
| 作者 | He, Liangliang1; Xu, Chunxia1; Wang, Ziying6; Duan, Shuyi2; Xu, Jinjin1; Li, Chuan5 ; Yao, Xinsheng1,3; Gonzalez, Frank J.4; Qin, Zifei1,2; Yao, Zhihong1,3,5
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| 刊名 | FRONTIERS IN PHARMACOLOGY
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| 出版日期 | 2022-08-04 |
| 卷号 | 13页码:17 |
| 关键词 | Xian-Ling-Gu-Bao capsule estrogens glucuronidation inhibitory effects UDP-glucuronosyltransferase |
| DOI | 10.3389/fphar.2022.935685 |
| 通讯作者 | Qin, Zifei(qzf1989@163.com) ; Yao, Zhihong(yaozhihong_jnu@163.com) |
| 英文摘要 | Xian-Ling-Gu-Bao (XLGB) capsule, a well-known traditional Chinese medicine prescription, is widely used for the treatment of osteoporosis. It could significantly increase the levels of estrogen in ovariectomized rats and mice. However, this working mechanism has not been well elucidated. Considering that UDP-glucuronosyltransferase (UGT) enzymes are the important enzymes that inactivate and regulate estrogen activity in vivo, this study aimed to identify the bioactive compounds from XLGB against the glucuronidation of estrogens. First, thirty compounds were considered as candidate bioactive compounds based on our previous studies including pharmacological evaluation, chemical profiles, and metabolic profiles. Second, the characteristics of estrogen glucuronidation by uridine diphosphate glucuronic acid (UDPGA)-supplemented human liver microsomes (HLM), human intestine microsomes (HIM), and expressed UGT enzymes were determined, and the incubation systems of their key UGT enzymes were optimized. Then, inhibitory effects and mechanisms of XLGB and its main compounds toward the key UGT isozymes were further investigated. As a result, estrogen underwent efficient glucuronidation by HLM and HIM. UGT1A10, 1A1, and 2B7 were mainly responsible for the glucuronidation of estrone, beta-estradiol, and estriol, respectively. For E1 and E2, UGT1A10 and 1A1 tended to mediate estrogen-3-O-glucuronidation, while UGT2B7 preferred catalyzing estrogen-16-O-glucuronidation. Furthermore, the incubation system for active UGT isoforms was optimized including Tris-HCl buffer, detergents, MgCl2 concentration, beta-glucuronidase inhibitors, UDPGA concentration, protein concentration, and incubation time. Based on optimal incubation conditions, eleven, nine, and nine compounds were identified as the potent inhibitors for UGT1A10, 1A1, and 2B7, respectively (IC50 < 4.97 mu M and K-i < 3.35 mu M). Among them, six compounds (bavachin, isobavachin, isobavachalcone, neobavaisoflavone, corylifol A, and icariside II) simultaneously demonstrated potent inhibitory effects against these three active enzymes. Prenylated flavanols from Epimedium brevicornu Maxim., prenylated flavonoids from Psoralea corylifolia L., and salvianolic acids from Salvia miltiorrhiza Bge. were characterized as the most important and effective compounds. The identification of potent natural inhibitors of XLGB against the glucuronidation of estrogen laid an important foundation for the pharmacodynamic material basis. |
| WOS关键词 | UDP-GLUCURONOSYLTRANSFERASE ENZYMES ; CHEMICAL-CONSTITUENTS ; 1ST MULTICENTER ; HERBAL FUFANG ; HEPATOTOXICITY ; ESTRIOL ; 1A1 |
| 资助项目 | National Natural Science Foundation of China ; Young Elite Scientists Sponsorship Program by Henan Association for Science and Technology ; Guangdong Basic and Applied Basic Research Foundation ; State Key Laboratory of Drug Research ; Foundation of Henan Educational Committee ; [81903704] ; [2022HYTP045] ; [2019A1515011285] ; [SIMM1903KF-07] ; [20A350012] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | FRONTIERS MEDIA SA |
| WOS记录号 | WOS:000891665000001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/304425]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Qin, Zifei; Yao, Zhihong |
| 作者单位 | 1.Jinan Univ, Coll Pharm, Guangzhou, Peoples R China 2.Zhengzhou Univ, Dept Pharm, Affiliated Hosp 1, Zhengzhou, Peoples R China 3.Jinan Univ, Int Cooperat Lab Tradit Chinese Med Modernizat & I, Minist PR China, Guangzhou, Peoples R China 4.NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD USA 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 6.Univ Bristol, Sch Chem, Bristol, England |
| 推荐引用方式 GB/T 7714 | He, Liangliang,Xu, Chunxia,Wang, Ziying,et al. Identification of naturally occurring inhibitors in Xian-Ling-Gu-Bao capsule against the glucuronidation of estrogens[J]. FRONTIERS IN PHARMACOLOGY,2022,13:17. |
| APA | He, Liangliang.,Xu, Chunxia.,Wang, Ziying.,Duan, Shuyi.,Xu, Jinjin.,...&Yao, Zhihong.(2022).Identification of naturally occurring inhibitors in Xian-Ling-Gu-Bao capsule against the glucuronidation of estrogens.FRONTIERS IN PHARMACOLOGY,13,17. |
| MLA | He, Liangliang,et al."Identification of naturally occurring inhibitors in Xian-Ling-Gu-Bao capsule against the glucuronidation of estrogens".FRONTIERS IN PHARMACOLOGY 13(2022):17. |
入库方式： OAI收割
来源：上海药物研究所
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