Screening Trimethoprim Primary Metabolites for Covalent Binding to Albumin.
Screening Trimethoprim Primary Metabolites for Covalent Binding to Albumin.
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DOI：
10.1007/s00044-020-02570-z
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发表时间：
2020-07
期刊：
影响因子：
--
通讯作者：
Goldman JL
中科院分区：
文献类型：
--
作者：
Nolte WM;Tessman RT;Goldman JL
药物和药物代谢产物对内源性蛋白质的修饰被认为是特异质药物不良反应（IADR）的原因。甲氧苄啶（TMP）是一种常见的处方抗生素，与IADR有关;然而，这种药物或其代谢产物修饰蛋白质的机制尚不清楚。本研究描述了甲氧苄啶及其主要代谢产物共价修饰人血清白蛋白（HSA）能力的筛选结果。筛选的第一步是化合物与HSA的体外反应，然后用对药物修饰的蛋白质具有特异性的抗血清进行蛋白质印迹。然后使用非靶向肽谱分析方法筛选在蛋白质印迹中具有阳性信号的化合物以发现修饰的肽。该策略确定了HSA中通过与TMP代谢产物α-羟基甲氧苄啶（Cα-OH-TMP）孵育而修饰的两个位点。
Modification of endogenous proteins by drugs and drug metabolites are thought to be a cause of idiosyncratic adverse drug reactions (IADRs). Trimethoprim (TMP) is a commonly prescribed antibiotic that has been implicated in IADRs; however, there is no known mechanism by which this drug or its metabolites modify proteins. This study describes the results of screening trimethoprim and its primary metabolites for the ability to covalently modify human serum albumin (HSA). The first step of the screen was in vitro reactions of the compounds with HSA followed by western blotting with antisera specific to drug-modified proteins. Compounds with positive signal in the western blot were then screened using an untargeted peptide profiling method to discover modified peptides. This strategy identified two sites in HSA that are modified by incubation with a TMP metabolite, α-hydroxy trimethoprim (Cα-OH-TMP).
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