Inhibitory Effect of Two Carbonic Anhydrases Inhibitors on the Activity of Major Cytochrome P450 Enzymes.

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Fawzy A Elbarbry, Tamer M Ibrahim, Mohamed A Abdelrahman, Claudiu T Supuran, Wagdy M Eldehna
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引用次数: 0

Abstract

Background and objectives: Both AW-9A (coumarin derivative) and WES-1 (sulfonamide derivative) were designed and synthesized as potential selective carbonic anhydrase inhibitors and were tested for anticancer activity. This study was undertaken to investigate their potential inhibitory effects on the major human cytochrome P450 (CYP) drug-metabolizing enzymes.

Methods: Specific CYP probe substrates and validated analytical methods were used to measure the activity of the tested CYP enzymes. Furthermore, in silico simulations were conducted to understand how AW-9A and WES-1 bind to CYP2A6 at a molecular level. Molecular docking experiments were performed using the high-resolution X-ray structure, Protein Data Bank (PDB) ID: 2FDV for CYP2A6.

Results: CYP2E1-catalyzed chlorzoxazone-6'-hydroxylation was strongly inhibited by AW-9A and WES-1 with IC50 values of 0.084 µM and 0.101 µM, respectively. CYP2A6-catalyzed coumarin-7'-hydroxylation was moderately inhibited by AW-9A (IC50 = 4.2 µM). CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzymes were weakly or negligibly inhibited by both agents. Docking studies suggest elevated potential to block the catalytic activity of CYP2A6.

Conclusions: These findings point to the feasibility of utilizing these agents as promising chemopreventive agents (owing to inhibition of CYP2E1), and AW-9A as a smoking cessation aid (owing to inhibition of CYP2A6). Additional in-vivo studies should be conducted to examine the impact of CYP2A6 and CYP2E1 inhibition on drug interactions with probe substrates of these enzymes.

Abstract Image

两种碳酸酐酶抑制剂对主要细胞色素 P450 酶活性的抑制作用。
背景和目的:AW-9A(香豆素衍生物)和 WES-1(磺胺衍生物)被设计合成为潜在的选择性碳酸酐酶抑制剂,并进行了抗癌活性测试。本研究旨在探讨它们对人类主要细胞色素 P450(CYP)药物代谢酶的潜在抑制作用:方法:使用特定的 CYP 探针底物和有效的分析方法来测量受测 CYP 酶的活性。此外,为了了解 AW-9A 和 WES-1 如何在分子水平上与 CYP2A6 结合,还进行了硅学模拟。利用 CYP2A6 的高分辨率 X 射线结构(蛋白质数据库(PDB)ID:2FDV)进行了分子对接实验:CYP2E1催化的氯唑沙宗-6'-羟基化反应受到 AW-9A 和 WES-1 的强烈抑制,IC50 值分别为 0.084 µM 和 0.101 µM。AW-9A 可中度抑制 CYP2A6 催化的香豆素-7'-羟化反应(IC50 = 4.2 µM)。两种制剂对 CYP1A2、CYP2C9、CYP2C19、CYP2D6 和 CYP3A4 酶的抑制作用较弱或可以忽略不计。对接研究表明,阻断 CYP2A6 催化活性的潜力较高:这些研究结果表明,将这些制剂用作有前途的化学预防制剂(由于抑制了 CYP2E1)以及将 AW-9A 用作戒烟辅助剂(由于抑制了 CYP2A6)是可行的。应进行更多的体内研究,以检查 CYP2A6 和 CYP2E1 抑制对药物与这些酶的探针底物相互作用的影响。
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来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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