Effects of tyrosine kinase inhibitors used for the treatment of non-small cell lung carcinoma on cytochrome P450 2J2 activities.

IF 1.3 4区医学 Q4 PHARMACOLOGY & PHARMACY

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-08-12 DOI:10.1080/00498254.2024.2389401

Ayaka Kojima, Masayuki Nadai, Norie Murayama, Hiroshi Yamazaki, Miki Katoh

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引用次数: 0

Abstract

Cytochrome P450 (CYP) 2J2 is responsible for the epoxidation of arachidonic acid, producing epoxyeicosatrienoic acids (EETs) that are known to enhance tumorigenesis. CYP2J2 is prominently expressed in the heart and also found in the lungs. Furthermore, the expression level of CYP2J2 in tumour tissues is higher than that in adjacent normal tissues. Non-small cell lung carcinoma is a common cancer, and tyrosine kinase inhibitors (TKIs) are powerful tools for its treatment. This study aimed to elucidate the inhibitory effects of 17 TKIs on CYP2J2 activity using LC-MS/MS.Seventeen TKIs exhibited different inhibitory effects on CYP2J2-catalysed astemizole O-demethylation in recombinant CYP2J2. Pralsetinib and selpercatinib showed strong competitive inhibition, with inhibition constant values of 0.48 and 1.1 µM, respectively. They also inhibited other CYP2J2 activities, including arachidonic acid epoxidation, hydroxyebastine carboxylation, and rivaroxaban hydroxylation.In conclusion, we showed that pralsetinib and selpercatinib strongly inhibit CYP2J2 activity. Inhibition of 14,15-EET production by these TKIs may be a novel mechanism for suppressing tumour growth and proliferation. Additionally, when these TKIs are co-administered with a CYP2J2 substrate, we may consider the possibility of drug-drug interactions via CYP2J2 inhibition.

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用于治疗非小细胞肺癌的酪氨酸激酶抑制剂对细胞色素 P450 2J2 活性的影响。

1.细胞色素 P450（CYP）2J2 负责花生四烯酸的环氧化作用，产生环二十碳三烯酸（EETs），众所周知，EETs 可促进肿瘤的发生。CYP2J2 在心脏和肺部都有显著表达。此外，肿瘤组织中 CYP2J2 的表达水平高于邻近的正常组织。非小细胞肺癌是一种常见的癌症，酪氨酸激酶抑制剂（TKIs）是治疗这种癌症的有力工具。本研究旨在利用 LC-MS/MS 技术阐明 17 种 TKIs 对 CYP2J2 活性的抑制作用。在重组 CYP2J2 中，17 种 TKIs 对 CYP2J2 催化的阿司咪唑 O-去甲基化表现出不同的抑制作用。普拉塞替尼和色瑞帕替尼表现出很强的竞争性抑制作用，抑制常数分别为 0.48 和 1.1 µM。它们还抑制了其他 CYP2J2 活性，包括花生四烯酸环氧化、羟基巴斯汀羧化和利伐沙班羟化。总之，我们发现普拉塞替尼和色瑞帕替尼对 CYP2J2 活性有很强的抑制作用。这些TKIs抑制14,15-EET的产生可能是抑制肿瘤生长和增殖的一种新机制。此外，当这些 TKIs 与 CYP2J2 底物联合用药时，我们可以考虑通过 CYP2J2 抑制发生药物间相互作用的可能性。

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

Xenobiotica 医学-毒理学

CiteScore

3.80

自引率

5.60%

发文量

审稿时长

2 months

期刊介绍： Xenobiotica covers seven main areas, including:General Xenobiochemistry, including in vitro studies concerned with the metabolism, disposition and excretion of drugs, and other xenobiotics, as well as the structure, function and regulation of associated enzymesClinical Pharmacokinetics and Metabolism, covering the pharmacokinetics and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in manAnimal Pharmacokinetics and Metabolism, covering the pharmacokinetics, and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in animalsPharmacogenetics, defined as the identification and functional characterisation of polymorphic genes that encode xenobiotic metabolising enzymes and transporters that may result in altered enzymatic, cellular and clinical responses to xenobioticsMolecular Toxicology, concerning the mechanisms of toxicity and the study of toxicology of xenobiotics at the molecular levelXenobiotic Transporters, concerned with all aspects of the carrier proteins involved in the movement of xenobiotics into and out of cells, and their impact on pharmacokinetic behaviour in animals and manTopics in Xenobiochemistry, in the form of reviews and commentaries are primarily intended to be a critical analysis of the issue, wherein the author offers opinions on the relevance of data or of a particular experimental approach or methodology