Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE Wageningen, The Netherlands.
Nutrients. 2022 Mar 24;14(7):1364. doi: 10.3390/nu14071364.
α-Dicarbonyl compounds, particularly methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG), are highly reactive precursors for the formation of advanced glycation end products (AGEs). They are formed in vivo and during food processing. This study aimed to investigate the role of intracellular glutathione (GSH) levels in the induction of Nrf2-mediated gene expression by α-dicarbonyl compounds. The reactions between α-dicarbonyl compounds (MGO, GO, and 3-DG) and GSH were studied by LC-MS in a cell-free system. It was shown that these three α-dicarbonyl compounds react instantaneously with GSH, with the GSH-mediated scavenging decreasing in the order MGO > GO > 3DG. Furthermore, in a cell-based reporter gene assay MGO, GO, and 3-DG were able to induce Nrf2-mediated gene expression in a dose-dependent manner. Modulation of intracellular GSH levels showed that the cytotoxicity and induction of the Nrf2-mediated pathway by MGO, GO and 3-DG was significantly enhanced by depletion of GSH, while a decrease in Nrf2-activation by MGO and GO but not 3-DG was observed upon an increase of the cellular GSH levels. Our results reveal subtle differences in the role of GSH in protection against the three typical α-dicarbonyl compounds and in their induction of Nrf2-mediated gene expression, and point at a dual biological effect of the α-dicarbonyl compounds, being reactive toxic electrophiles and -as a consequence- able to induce Nrf2-mediated protective gene expression, with MGO being most reactive.
α-二羰基化合物，特别是甲基乙二醛（MGO）、乙二醛（GO）和 3-脱氧葡萄糖酮（3-DG），是高级糖基化终产物（AGEs）形成的高反应性前体。它们在体内和食品加工过程中形成。本研究旨在探讨细胞内谷胱甘肽（GSH）水平在α-二羰基化合物诱导 Nrf2 介导的基因表达中的作用。在无细胞体系中通过 LC-MS 研究了α-二羰基化合物（MGO、GO 和 3-DG）与 GSH 的反应。结果表明，这三种α-二羰基化合物与 GSH 立即反应，GSH 介导的清除作用按 MGO>GO>3DG 的顺序降低。此外，在基于细胞的报告基因测定中，MGO、GO 和 3-DG 能够以剂量依赖的方式诱导 Nrf2 介导的基因表达。细胞内 GSH 水平的调节表明，MGO、GO 和 3-DG 通过 GSH 的耗竭显著增强了细胞毒性和 Nrf2 介导的途径诱导，而细胞内 GSH 水平的增加则导致 MGO 和 GO 而非 3-DG 的 Nrf2 激活减少。我们的结果揭示了 GSH 在保护免受三种典型的α-二羰基化合物和诱导 Nrf2 介导的基因表达中的作用存在细微差异，并指出α-二羰基化合物具有双重生物学效应，既是反应性的毒性亲电试剂，因此能够诱导 Nrf2 介导的保护性基因表达，其中 MGO 最具反应性。
