Time-dependent inactivation of human cytochrome P450 2A6 variants and 2A13 by imperatorin: natural coumarins and imperatorin oxidation.

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2025-07-12 DOI:10.1016/j.bcp.2025.117155

Yune-Fang Ueng, Jia-Shan Chih, Wen-Tai Li, An-Chi Chen, Keng-Chang Tsai, Chia-Ching Liaw, Kaun-Wen Chen, Pei-Syuan Chen, Chu Lin Hsiao

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引用次数: 0

Abstract

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.

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欧前胡素对人细胞色素P450 2A6变体和2A13的时间依赖性失活：天然香豆素和欧前胡素氧化。

欧前胡素等结构多样的香豆素广泛分布于食用和药用植物中。本研究旨在探讨13种天然香豆素对人细胞色素P450 (CYP) 2A6变异和CYP2A13重组系统中基因型相关的时间依赖性抑制（TDI）及欧前胡素强效TDI的机制。与补骨脂素相比，甲氧基和烯基的加入增强了野生型CYP2A6.1的代谢依赖性抑制。羟基化呋喃香豆素、异欧前胡素、5-甲氧基-8-羟基补骨脂素和黄嘌呤醇对CYP2A13有抑制作用，但对CYP2A6.1没有抑制作用。含有前置氧基的欧前胡素对CYP2A6.1/2A13的抑制作用较强，而对CYP2A6.10的影响较小。与欧前胡素不同，当归素比CYP2A6.1更有效地抑制CYP2A6.10。通过谷胱甘肽偶联可降低欧前胡素诱导的CYP2A6.1/2A13的TDI，但透析或铁氰化钾不能降低TDI。欧前胡素氧化产生与CYP2A6.1的代谢物中间复合物。欧前胡素与CYP2A13的失活效率比与CYP2A6.1的失活效率高33%，与CYP2A13的呋烷环氧化效率比CYP2A6.1高4倍一致。而CYP2A6.10的呋喃酰环氧化效率为CYP2A6.1的18%。最佳对接模型显示，在CYP2A13中，欧前胡素的前酰氧基部分位于血红素基团附近，而在CYP2A6.1中不位于血红素基团附近，这支持了CYP2A13对欧前胡素14-羟基化的更高效率。总之，香豆素在CYP2A6/2A13抑制中表现出不同的时间依赖性、异构体偏好和不同的抗性。欧前胡素对CYP2A13和CYP2A6.10的抑制程度分别高于和低于CYP2A6.1，这取决于呋喃基环氧化效率。香豆素对CYP2As的结构依赖性和基因型相关性抑制应在进一步的获益/毒性评估中加以考虑。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.