Cytochrome P450 oxidoreductase variant A503V contributes to the increased CYP3A5 activity with tacrolimus in vitro.

IF 3.9 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Expert Opinion on Drug Metabolism & Toxicology Pub Date : 2022-07-01 Epub Date: 2022-08-17 DOI:10.1080/17425255.2022.2112174

Yuan Gao, Jingjing Ma

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引用次数: 0

Abstract

Background: Tacrolimus is a immunosuppressant drug in transplantation with a narrow therapeutic range and high pharmacokinetic variability. Clinical studies have revealed that POR*28 contributes enhanced tacrolimus clearance in CYP3A5 expressers. However, it remains unknown that how exactly the POR polymorphism could influence the metabolism of tacrolimus via CYP3A5 in vitro.

Research design & methods: A503V is an amino acid sequence variant encoded by POR*28. Wild-type (WT) and A503V POR, with WT CYP3A5 were expressed in recombinant HepG2 cells and reconstituted proteins. Michaelis constant (K_m) and maximum velocity (V_max) of CYP3A5 with tacrolimus as substrates were determined, and catalytic efficiency is expressed as V_max/K_m.

Results: Both WT and A503V POR down-regulated the CYP3A5 mRNA expression, and WT POR rather than A503V down-regulated the protein expression of CYP3A5 in recombinant HepG2 cells. Compared with WT POR, A503V increased metabolism of tacrolimus by CYP3A5 in both cellular and protein levels.

Conclusion: A503V can affect CYP3A5-catalyzed tacrolimus metabolism in vitro, which suggests that A503V has the potential to serve as a biomarker for tacrolimus treatment in transplantation recipients.

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细胞色素P450氧化还原酶变体A503V有助于他克莫司体外增加CYP3A5活性。

背景:他克莫司是一种移植免疫抑制剂，治疗范围窄，药代动力学变异性大。临床研究表明，POR*28有助于增强CYP3A5表达者对他克莫司的清除率。然而，POR多态性在体外如何通过CYP3A5影响他克莫司的代谢尚不清楚。研究设计与方法:A503V是由POR*28编码的氨基酸序列变体。在重组HepG2细胞中表达野生型(WT)和A503V型POR以及WT型CYP3A5重组蛋白。测定了以他克莫司为底物的CYP3A5的米切里斯常数(Km)和最大速度(Vmax)，催化效率用Vmax/Km表示。结果:WT和A503V POR均下调了重组HepG2细胞CYP3A5 mRNA的表达，且WT POR比A503V POR下调了重组HepG2细胞CYP3A5蛋白的表达。与WT POR相比，A503V通过CYP3A5在细胞和蛋白水平上增加了他克莫司的代谢。结论:A503V可影响cyp3a5催化的他克莫司体外代谢，提示A503V有潜力作为移植受体他克莫司治疗的生物标志物。

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

Expert Opinion on Drug Metabolism & Toxicology 医学-生化与分子生物学

CiteScore

7.90

自引率

2.30%

发文量

审稿时长

4-8 weeks

期刊介绍： Expert Opinion on Drug Metabolism & Toxicology (ISSN 1742-5255 [print], 1744-7607 [electronic]) is a MEDLINE-indexed, peer-reviewed, international journal publishing review articles on all aspects of ADME-Tox. Each article is structured to incorporate the author’s own expert opinion on the scope for future development. The Editors welcome: Reviews covering metabolic, pharmacokinetic and toxicological issues relating to specific drugs, drug-drug interactions, drug classes or their use in specific populations; issues relating to enzymes involved in the metabolism, disposition and excretion of drugs; techniques involved in the study of drug metabolism and toxicology; novel technologies for obtaining ADME-Tox data. Drug Evaluations reviewing the clinical, toxicological and pharmacokinetic data on a particular drug. The audience consists of scientists and managers in the pharmaceutical industry, pharmacologists, clinical toxicologists and related professionals.