Time-dependent inactivation of human cytochrome P450 2A6 variants and 2A13 by imperatorin: natural coumarins and imperatorin oxidation
學年 114
學期 1
出版（發表）日期 2025-11-01
作品名稱 Time-dependent inactivation of human cytochrome P450 2A6 variants and 2A13 by imperatorin: natural coumarins and imperatorin oxidation
作品名稱（其他語言）
著者 Yune-Fang Ueng; Jia-Shan Chih; Wen-Tai Li; An-Chi Chen; Keng-Chang Tsai; Chia-Ching Liaw; Kuan-Wen Chen; Pei-Syuan Chen; Chu Lin Hsiao
單位
出版者
著錄名稱、卷期、頁數 Biochemical Pharmacology 241, 117155
摘要 Structurally diverse coumarins such as imperatorin are widely distributed in edible and medicinal plants. This study aimed to investigate the genotype-associated time-dependent inhibition (TDI) induced by 13 natural coumarins and the mechanism of potent TDI by imperatorin in recombinant systems of human cytochrome P450 (CYP) 2A6 variants and CYP2A13. Compared with psoralen, the addition of methoxy and alkenyl groups enhanced the metabolism-dependent inhibition of the wild type CYP2A6.1. Hydroxylated furanocoumarins, alloisoimperatorin, 5-methoxy-8-hydroxypsoralen, and xanthotoxol, inhibited CYP2A13 but not CYP2A6.1. Imperatorin, which carries a prenyloxy group, strongly inhibited CYP2A6.1/2A13, whereas CYP2A6.10 was less affected. Unlike imperatorin, angelicin inhibited CYP2A6.10 more potently than CYP2A6.1. The imperatorin-induced TDI of CYP2A6.1/2A13 was reduced by glutathione conjugation, but not by dialysis or potassium ferricyanide. Imperatorin oxidation generated a metabolite-intermediate complex with CYP2A6.1. Imperatorin exerted a 33% higher inactivation efficiency with CYP2A13 than that with CYP2A6.1, consistent with the 4-fold higher furanyl epoxidation efficiency of CYP2A13 compared to CYP2A6.1. However, the furanyl epoxidation efficiency of CYP2A6.10 was 18% that of CYP2A6.1. The best docking model revealed that the prenyloxy moiety of imperatorin was located close to the heme group in CYP2A13, but not in CYP2A6.1, which supported the higher efficiency of imperatorin 14-hydroxylation by CYP2A13. In summary, coumarins exhibited differential time-dependence, isoform preference, and variant resistance in CYP2A6/2A13 inhibition. Imperatorin inhibited CYP2A13 and CYP2A6.10 to greater and lesser extents, respectively, than CYP2A6.1, depending on furanyl epoxidation efficiency. Structure-dependent and genotype-associated inhibition of CYP2As by coumarins should be considered in further benefit/toxicity evaluations.
關鍵字
語言 en
ISSN 1873-2968; 0006-2952
期刊性質 國外
收錄於 SCI
產學合作
通訊作者
審稿制度 否
國別 USA
公開徵稿
出版型式 ,電子版,紙本
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機構典藏連結 ( http://tkuir.lib.tku.edu.tw:8080/dspace/handle/987654321/129595 )