呼气中代谢挥发物测定药物反应的研究:gstacamine作为未标记底物测量CYP3A4活性

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-08-25 DOI:10.1002/cmdc.202500492
Valentina Stock, Rebecca Hofer, Klaus R. Liedl, Jakob Troppmair, Thierry Langer, Hubert Gstach, Christian Dank, Sarah Kammerer, Veronika Ruzsanyi
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引用次数: 0

摘要

呼吸分析是一种很有前途的无创诊断工具,但呼吸测试的临床适用性取决于几个因素。一个显著的标准涉及到在代谢过程中产生可检测的挥发性代谢物的能力底物的存在。在这项工作中,我们评估了两种候选化合物的潜力,即gstachidine和gstachamine,用于代谢呼吸分析。这两种底物在过表达CYP3A4的HepG2细胞克隆中的毒性和代谢转化进行了评估。研究发现,Gstachidine是有毒的,不产生任何挥发性代谢物。相比之下,谷胱甘胺成功地产生了作为挥发性代谢物的丁酮,使其成为第一个产生稳定的挥发性有机化合物的底物,只有在呼吸中的低ppbV水平下才能检测到。为了表征其生物转化,我们进行了时间依赖性分析,以及CYP特异性、毒性和对n -脱烷基胃胱甘胺或丁酮生产的抑制研究。结果表明,在特定n -脱烷基代谢物的产生中,谷胱甘肽具有较高的代谢转化率和强烈的cyp3a4依赖性。此外,在使用CYP抑制剂1-氨基苯并三唑或酮康唑治疗后,HepG2-CYP3A4细胞中两种代谢物的产生均显著减少。结果表明,胃胱胺具有无创监测CYP3A4代谢的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Towards the Use of Metabolic Volatiles in Breath for Determining Drug Response: Gstachamine as an Unlabeled Substrate to Measure CYP3A4 Activity

Towards the Use of Metabolic Volatiles in Breath for Determining Drug Response: Gstachamine as an Unlabeled Substrate to Measure CYP3A4 Activity

Breath analysis is a promising noninvasive diagnostic tool, but the clinical applicability of breath tests depends on several factors. A salient criterion pertains to the presence of substrates with the ability to produce detectable volatile metabolites during the metabolism. In this work, we evaluated the potential of two candidate compounds, namely gstachidine and gstachamine, for their use in metabolic breath analysis. Both substrates were evaluated for their toxicity and metabolic conversion in HepG2 cell clones overexpressing CYP3A4. Gstachidine was found to be toxic and did not produce any volatile metabolite. In contrast, gstachamine successfully generated butanone as a volatile metabolite, making it the first substrate to yield a stable VOC detectable exclusively at low ppbV levels in breath. To characterize its biotransformation, we conducted time-dependent analyses, as well as CYP specificity, toxicity, and inhibition investigations regarding the production of N-dealkylated gstachamine or butanone. The results demonstrated that gstachamine had a high metabolic turnover and a strong CYP3A4-dependency in the production of the specific N-dealkylated metabolite. Furthermore, a substantial reduction in the production of both metabolites was observed in HepG2-CYP3A4 cells following treatment with CYP inhibitors 1-aminobenzotriazole or ketoconazole. The results suggest that gstachamine has potential for noninvasive CYP3A4 metabolism monitoring.

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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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