对 3-苯氧基苯甲酸及其代谢产物的毒理效应和生物活性进行的硅学研究。

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY
Xenobiotica Pub Date : 2024-06-01 Epub Date: 2024-06-24 DOI:10.1080/00498254.2024.2361457
Hai Duc Nguyen, Thuy Linh Hoang, Giang Huong Vu
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引用次数: 0

摘要

我们的目的是阐明3-苯氧基苯甲酸(3PBA)及其代谢产物的毒性作用和生物活性。我们采用了大量的硅学方法来确定 3PBA 的毒性作用和生物活性,包括 PASS 在线、分子对接、ADMETlab 2.0、ADMESWISS、MetaTox 和分子动力学模拟。通过第二阶段反应(O-葡萄糖醛酸化、O-硫酸化和甲基化)确定了 10 种代谢产物。所有被研究的化合物都遵循利宾斯基规则,表明它们是刺激剂或危险过程的诱导剂。由于所研究的化合物具有较高的胃肠道吸收率和到达血脑屏障的能力,其物理化学和药代动力学特性与现有的有害影响证据相吻合,包括吐血、生殖功能障碍、过敏性皮炎、毒性呼吸和神经毒性。所研究的化合物与细胞凋亡途径、生殖系统、神经内分泌干扰物、磷脂转运 ATP 酶抑制剂和 JAK2 表达有关。与 3PBA 和其他代谢产物相比,一种 O-葡萄糖醛酸化代谢产物与 CYP2C9、CYP3A4、caspase 3 和 caspase 8 的结合亲和力和相互作用更高,而甲基化代谢产物占主导地位,毒性更大。在确定 3PBA 对其他器官(肝脏、肾脏)的有害影响之前,还需要进行更多的研究。未来的研究方向可能包括对硅学预测进行实验验证、阐明分子机制和探索治疗干预措施。这些发现有助于我们了解 3PBA 及其代谢物的毒理学特征,从而对风险评估和监管决策产生影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
An in silico investigation of the toxicological effects and biological activities of 3-phenoxybenzoic acid and its metabolite products.

We aimed to elucidate the toxic effects and biological activities of 3-phenoxybenzoic acid (3PBA) and its metabolite products.

Numerous in silico methods were used to identify the toxic effects and biological activities of 3PBA, including PASS online, molecular docking, ADMETlab 2.0, ADMESWISS, MetaTox, and molecular dynamic simulation.

Ten metabolite products were identified via Phase II reactions (O-glucuronidation, O-sulfation, and methylation).

All of the investigated compounds were followed by Lipinski's rule, indicating that they were stimulants or inducers of hazardous processes.

Because of their high gastrointestinal absorption and ability to reach the blood-brain barrier, the studied compounds' physicochemical and pharmacokinetic properties matched existing evidence of harmful effects, including haematemesis, reproductive dysfunction, allergic dermatitis, toxic respiration, and neurotoxicity.

The studied compounds have been linked to the apoptotic pathway, the reproductivity system, neuroendocrine disruptors, phospholipid-translocating ATPase inhibitors, and JAK2 expression.

An O-glucuronidation metabolite product demonstrated higher binding affinity and interaction with CYP2C9, CYP3A4, caspase 3, and caspase 8 than 3PBA and other metabolite products, whereas metabolite products from methylation were predominant and more toxic.

Our in silico findings partly meet the 3Rs principle by minimizing animal testing before more study is needed to identify the detrimental effects of 3PBA on other organs (liver, kidneys).

Future research directions may involve experimental validation of in silico predictions, elucidation of molecular mechanisms, and exploration of therapeutic interventions.

These findings contribute to our understanding of the toxicological profile of 3PBA and its metabolites, which has implications for risk assessment and regulatory decisions.

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来源期刊
Xenobiotica
Xenobiotica 医学-毒理学
CiteScore
3.80
自引率
5.60%
发文量
96
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
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