Bergaptol, a mechanism-based inactivator of CYP2C9

被引：4

作者：

Jiang, Tingting ^{[1
,2
]}

Cheng, Ting ^{[1
,2
]}

Li, Jing ^{[1
,2
]}

Zhou, Mengyue ^{[1
,2
]}

Tan, Rong ^{[1
,2
]}

Yang, Xiaojing ^{[3
]}

Wang, Yang ^{[1
,2
]}

Li, Weiwei ^{[1
,2
]}

Zheng, Jiang ^{[1
,2
,3
,4
]}

机构：

[1] Guizhou Med Univ, State Key Lab Funct & Applicat Med Plants, Guizhou Prov Key Lab Pharmaceut, Guiyang 550004, Guizhou, Peoples R China

[2] Guizhou Med Univ, Sch Pharm, Guiyang 550004, Guizhou, Peoples R China

[3] Shenyang Pharmaceut Univ, Sch Pharm, Wuya Coll Innovat, Shenyang 550025, Liaoning, Peoples R China

[4] Guizhou Med Univ, Key Lab Environm Pollut Monitoring & Dis Control, Minist Educ, Guiyang 550025, Guizhou, Peoples R China

来源：

MEDICINAL CHEMISTRY RESEARCH | 2020年 / 29卷 / 07期

基金：

中国国家自然科学基金;

关键词：

Grapefruit; Bergaptol (BGT); Mechanism-based inactivation (MBI); Grape-drug interaction; GRAPEFRUIT JUICE; CYTOCHROME-P450; BIOSYNTHESIS; DERIVATIVES; INHIBITION; ENZYMES; 2C9;

D O I：

10.1007/s00044-020-02564-x

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Grapefruit-mediated fruit-drug interaction has been well discussed in clinical practice. However, the biochemical mechanisms for such interaction are far beyond our understanding. The objectives of the present study aimed at the interaction between bergaptol (BGT) and CYP2C9. BGT, one of the major furanocoumarin constituents in grapefruit, has been reported to inhibit the activity of CYP2C9. And a number of furan-containing compounds are known to act as mechanism-based inactivators of CYP2C9. In this study, BGT was found to induce time-, concentration-, and NADPH-dependent irreversible inhibition of CYP2C9. A GSH conjugate was detected in an incubation mixture containing CYP2C9, BGT, NADPH, and GSH. Further mechanistic investigation revealed that a gamma-ketoenal metabolite was responsible for the enzyme inactivation. The obtained data indicate that BGT was a mechanism-based inactivator of CYP2C9. The study would facilitate the understanding of the mechanistic insight into fruit-drug interactions mediated by grapefruits.

引用

页码：1230 / 1237

页数：8

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