Quantitation of γ-Glutamylcysteine–Formaldehyde Conjugate in Formaldehyde- and Oxidative Stress-Exposed Cells by Liquid Chromatography–Tandem Mass Spectrometry,Chemical Research in Toxicology

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Quantitation of γ-Glutamylcysteine–Formaldehyde Conjugate in Formaldehyde- and Oxidative Stress-Exposed Cells by Liquid Chromatography–Tandem Mass Spectrometry
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2021-07-01 , DOI: 10.1021/acs.chemrestox.1c00113
Yao Zhao ₁ , Wan Chan ₁

Affiliation

Humans are constantly exposed to formaldehyde (FA) of both exogenous and endogenous sources, and FA exposure is associated with the development of many human diseases, including cancers. Marker molecules that can provide information on exposure history and amounts will assist disease risk assessment and early interventions. To develop marker signatures of FA exposure, we explored in this study the conjugation reaction of FA with γ-glutamylcysteine (GGC), one of the precursors to glutathione biosynthesis, under physiologically relevant conditions. The results showed that the reaction produced a stable metabolite of FA, (S)-1-((((R)-2-amino-2-carboxyethyl)thio)methyl)-5-oxopyrrolidine-2-carboxylic acid (COCA). Using liquid chromatography–tandem mass spectrometry coupled to a stable isotope-dilution method, we then quantitated for the first time the formation of this novel metabolite in FA- and Fe²⁺-EDTA-exposed human cells. The results revealed the exposure time- and concentration-dependent formation of COCA in FA- or Fe²⁺-EDTA-exposed cells, suggesting that COCA may serve as a biomarker of FA and oxidative stress exposure. Furthermore, the study sheds light on a previously unknown protective role of GGC against FA and oxidative stress.

中文翻译：

通过液相色谱-串联质谱法定量甲醛和氧化应激暴露细胞中的 γ-谷氨酰半胱氨酸-甲醛偶联物

人类不断暴露于外源性和内源性来源的甲醛 (FA)，而 FA 暴露与许多人类疾病的发展有关，包括癌症。可以提供有关暴露历史和数量信息的标记分子将有助于疾病风险评估和早期干预。为了开发 FA 暴露的标记特征，我们在本研究中探索了 FA 与 γ-谷氨酰半胱氨酸 (GGC)（谷胱甘肽生物合成的前体之一）在生理相关条件下的缀合反应。结果表明，该反应产生了稳定的 FA 代谢物，( S )-1-(((( R)-2-氨基-2-羧乙基)硫代)甲基)-5-氧代吡咯烷-2-羧酸(COCA)。然后，我们使用液相色谱-串联质谱联用稳定同位素稀释法，首次对暴露于 FA 和 Fe ²⁺ -EDTA 的人体细胞中这种新型代谢物的形成进行了定量。结果揭示了暴露于FA或 Fe ²⁺ -EDTA 的细胞中 COCA 的暴露时间和浓度依赖性形成，表明 COCA 可作为 FA 和氧化应激暴露的生物标志物。此外，该研究揭示了 GGC 对 FA 和氧化应激的先前未知的保护作用。

更新日期：2021-07-19

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