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人细胞色素 P450 参与氟氯西林生物活化的动力学特征：磺胺甲恶唑对 CYP3A 催化的羟化反应的抑制作用。

Characterization of kinetics of human cytochrome P450s involved in bioactivation of flucloxacillin: inhibition of CYP3A-catalysed hydroxylation by sulfaphenazole.

机构信息

Division of Molecular Toxicology, Amsterdam Institute for Molecules Medicine and Systems (AIMMS), Vrije Universiteit, Amsterdam, The Netherlands.

出版信息

Br J Pharmacol. 2019 Feb;176(3):466-477. doi: 10.1111/bph.14548. Epub 2018 Dec 26.

DOI:10.1111/bph.14548
PMID:30447161
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6329626/
Abstract

BACKGROUND AND PURPOSE

The aim of this study was to characterize the human cytochrome P450s (CYPs) involved in oxidative bioactivation of flucloxacillin to 5-hydroxymethyl flucloxacillin, a metabolite with high cytotoxicity towards biliary epithelial cells.

EXPERIMENTAL APPROACH

The CYPs involved in hydroxylation of flucloxacillin were characterized using recombinant human CYPs, pooled liver microsomes in the presence of CYP-specific inhibitors and by correlation analysis using a panel of liver microsomes from 16 donors.

KEY RESULTS

Recombinant CYPs showing the highest specific activity were CYP3A4, CYP3A7 and to lower extent CYP2C9 and CTP2C8. Michaelis-Menten enzyme kinetics were determined for pooled human liver microsomes, recombinant CYP3A4, CYP3A7 and CYP2C9. Surprisingly, sulfaphenazole appeared to be a potent inhibitor of 5'-hydroxylation of flucloxacillin by both recombinant CYP3A4 and CYP3A7.

CONCLUSIONS AND IMPLICATIONS

The combined results show that the 5'-hydroxylation of flucloxacillin is primarily catalysed by CYP3A4, CYP3A7 and CYP2C9. The large variability of the hepatic expression of these enzymes could affect the formation of 5'-hydroxymethyl flucloxacillin, which may determine the differences in susceptibility to flucloxacillin-induced liver injury. Additionally, the strong inhibition in CYP3A-catalysed flucloxacillin metabolism by sulfaphenazole suggests that unanticipated drug-drug interactions could occur with coadministered drugs.

摘要

背景与目的

本研究旨在研究人细胞色素 P450（CYP）在氟氯西林氧化生物转化为 5-羟甲基氟氯西林中的作用，后者是一种对胆管上皮细胞具有高细胞毒性的代谢物。

实验方法

使用重组人 CYP、在 CYP 特异性抑制剂存在下的混合肝微粒体以及使用来自 16 个供体的肝微粒体的相关分析来表征参与氟氯西林羟化的 CYP。

主要结果

显示出最高特异性活性的重组 CYP 为 CYP3A4、CYP3A7 和较低程度的 CYP2C9 和 CTP2C8。对混合人肝微粒体、重组 CYP3A4、CYP3A7 和 CYP2C9 进行了米氏酶动力学测定。令人惊讶的是，磺胺甲恶唑似乎是重组 CYP3A4 和 CYP3A7 催化氟氯西林 5'-羟化的有效抑制剂。

结论和意义

综合结果表明，氟氯西林的 5'-羟化主要由 CYP3A4、CYP3A7 和 CYP2C9 催化。这些酶在肝脏中的表达存在很大的可变性，这可能会影响 5'-羟甲基氟氯西林的形成，从而决定对氟氯西林诱导的肝损伤的易感性差异。此外，磺胺甲恶唑对 CYP3A 催化的氟氯西林代谢的强烈抑制表明，与同时使用的药物可能会发生意想不到的药物相互作用。

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