Probing and gauging of D-Penicillamine xenobiotics in hepatic Wilson disease patients

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Biophysical chemistry Pub Date : 2024-08-05 DOI:10.1016/j.bpc.2024.107306
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Abstract

D-penicillamine (PA) is the primary chelator of choice to treat Wilson disease (WD). There are limitations in obtaining comprehensive data on PA metabolites in biological specimens by conventional approaches. Hence, the aim of the present was to identify the major hepatic PA metabolites and draw clear conclusions of the drug's xenobiotic in WD. Urine samples were collected from children with hepatic WD (n = 63, aged 14.8 ± 4 years) 5 h after PA administration (16.3 ± 3.8 mg/kg/day) and age-matched healthy volunteers comprised as controls (n = 30). High-resolution 800 MHz nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry was applied to reveal unambiguous appraisals of different excretory by-products of PA metabolism. Four new products comprising penicillamine disulphide (PD), penicillamine cysteine disulphide (PCD), S-methyl penicillamine (SMP), and N-acetyl penicillamine (NAP) of PA xenobiotic metabolites were identified using high-resolution NMR spectroscopy. Quantitative levels of PCD and SMP were approximately three-fold higher than those of PD and NAP, respectively. High-resolution NMR identifies the major PA metabolites with certainty. Reduction, sulfation, and methylation are the predominant pathways of PA metabolism. There is a potential application for assessing therapeutic monitoring of chelation in hepatic WD.

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肝性威尔逊病患者体内 D-青霉胺异生物体的探查和测量。
D-青霉胺(PA)是治疗威尔逊病(WD)的主要螯合剂。传统方法难以获得生物样本中 PA 代谢物的全面数据。因此,本研究旨在确定 PA 的主要肝脏代谢物,并就该药物在 WD 中的异生物性得出明确结论。研究人员收集了肝性 WD 患儿(63 人,年龄为 14.8 ± 4 岁)在服用 PA(16.3 ± 3.8 毫克/千克/天)5 小时后的尿液样本,以及年龄匹配的健康志愿者对照组(30 人)的尿液样本。应用高分辨率 800 MHz 核磁共振波谱(NMR)和质谱法对 PA 代谢的不同排泄副产物进行了明确评估。利用高分辨率核磁共振光谱鉴定了 PA 异生物代谢物的四种新产物,包括青霉胺二硫化物(PD)、青霉胺半胱氨酸二硫化物(PCD)、S-甲基青霉胺(SMP)和 N-乙酰青霉胺(NAP)。PCD和SMP的定量水平分别比PD和NAP高出约三倍。高分辨率核磁共振能确定 PA 的主要代谢物。还原、硫化和甲基化是 PA 代谢的主要途径。该方法可用于评估肝WD的螯合治疗监测。
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来源期刊
Biophysical chemistry
Biophysical chemistry 生物-生化与分子生物学
CiteScore
6.10
自引率
10.50%
发文量
121
审稿时长
20 days
期刊介绍: Biophysical Chemistry publishes original work and reviews in the areas of chemistry and physics directly impacting biological phenomena. Quantitative analysis of the properties of biological macromolecules, biologically active molecules, macromolecular assemblies and cell components in terms of kinetics, thermodynamics, spatio-temporal organization, NMR and X-ray structural biology, as well as single-molecule detection represent a major focus of the journal. Theoretical and computational treatments of biomacromolecular systems, macromolecular interactions, regulatory control and systems biology are also of interest to the journal.
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