Nordihydroguaiaretic acid inhibits glyoxalase I, and causes the accumulation of methylglyoxal followed by cell-growth inhibition
Nordihydroguaiaretic acid inhibits glyoxalase I, and causes the accumulation of methylglyoxal followed by cell-growth inhibition
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DOI：
10.1007/s11033-022-07929-6
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发表时间：
2022-09
影响因子：
2.8
通讯作者：
Masahiro Watanabe;Takao Toyomura;R. Ikegami;Yui Suwaki;Minami Sada;H. Wake;T. Nishinaka;O. Hatipoglu;Hideo Takahashi;M. Nishibori;S. Mori
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文献类型：
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作者：
Masahiro Watanabe;Takao Toyomura;R. Ikegami;Yui Suwaki;Minami Sada;H. Wake;T. Nishinaka;O. Hatipoglu;Hideo Takahashi;M. Nishibori;S. Mori
背景甲基乙二醛(MGO)是一种已知的糖酵解的毒性副产物，MGO诱导的细胞毒性被认为与多种疾病的发病有关。乙二酸酶I(GLO1)是哺乳动物细胞中清除MGO的关键酶，因此，影响GLO1活性的化合物是治疗MGO所致疾病的潜在药物。此前，我们发现去甲二氢愈创木酸(NDGA)是一种有效的GLO1抑制剂。结果NDGA对EA.hy926细胞的GLO1酶活性有明显的抑制作用，且呈剂量依赖性。它的Ki值估计比已知的GLO1抑制剂杨梅素低146倍。在细胞中加入MGO和NDGA后，细胞的生长受到明显的抑制，表明NGA对GLO1的抑制导致了足以影响细胞生长的MGO的积累。这些结果得到以下结果的支持：加入典型的MGO清除剂氨基胍可以显著逆转MGO和NDGA共同作用对细胞生长的抑制，并且在MGO和NDGA共同作用的过程中，细胞内MGO衍生的AGEs增加。结论NDGA是一种新的、有效的GLO1抑制剂。NDGA和MGO共同加入细胞后，细胞内MGO积累量增加，细胞生长抑制增强。
BackgroundMethylglyoxal (MGO) is a known toxic byproduct of glycolysis, with MGO-induced cytotoxicity believed to contribute to the pathogenesis of several diseases. Glyoxalase I (GLO1) is a key enzyme for eliminating MGO in mammalian cells, therefore, compounds affecting GLO1 activity are potential therapeutic agents for MGO-induced disorders. Previously, we found nordihydroguaiaretic acid (NDGA) as a potent GLO1 inhibitor.MethodsThe inhibitory characteristics of NDGA were determined spectrophotometrically with recombinant GLO1. NDGA-induced growth-inhibition and accumulation of MGO-derived advanced glycation end products (AGEs) were examined in EA.hy926 cells.ResultsNDGA showed significant inhibition of GLO1 enzymatic activity in a dose-dependent manner. Its Kivalue was estimated to be 146-fold lower than that of myricetin, a known GLO1 inhibitor. The co-addition of MGO with NDGA to the cells resulted in significant growth inhibition, suggesting that MGO accumulation, sufficient to affect cell growth, was caused by NDGA inhibiting GLO1. These findings were supported by the observations that the addition of aminoguanidine, a typical MGO scavenger, significantly reversed cell-growth inhibition by co-addition of MGO with NDGA, and that an increase in intracellular MGO-derived AGEs was observed during incubation with the co-addition of MGO with NDGA.ConclusionNDGA was found to be a novel and potent inhibitor of GLO1. The co-addition of NDGA with MGO to the cells resulted in increased intracellular MGO accumulation followed by enhanced cell-growth inhibition.