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Nordihydroguaiaretic acid inhibits glyoxalase I, and causes the accumulation of methylglyoxal followed by cell-growth inhibition

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Abstract

Background

Methylglyoxal (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.

Methods

The 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.

Results

NDGA showed significant inhibition of GLO1 enzymatic activity in a dose-dependent manner. Its Ki value 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.

Conclusion

NDGA 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.

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Data Availability

The data generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code Availability

Not applicable.

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Acknowledgements

This study was supported by JSPS KAKENHI Grant Numbers 21K06657 and 21K06701, the Sanyo Broadcasting Foundation, the Wesco Scientific Promotion Foundation, and the Ryobi Teien Memory Foundation.

Funding

JSPS KAKENHI Grant Numbers 21K06657 and 21K06701, the Sanyo Broadcasting Foundation, the Wesco Scientific Promotion Foundation, and the Ryobi Teien Memory Foundation.

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Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-Ku, 703-8516, Okayama, Japan

    Masahiro Watanabe, Takao Toyomura, Ryo Ikegami, Yui Suwaki, Minami Sada & Shuji Mori

  2. Department of Pharmacology, Faculty of Medicine, Kindai University, 589-8511, Osaka-Sayama, Japan

    Hidenori Wake, Takashi Nishinaka, Omer Faruk Hatipoglu & Hideo Takahashi

  3. Department of Pharmacology, Dentistry, and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 700-8558, Okayama, Japan

    Masahiro Nishibori

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  1. Masahiro Watanabe
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Correspondence to Shuji Mori.

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Watanabe, M., Toyomura, T., Ikegami, R. et al. Nordihydroguaiaretic acid inhibits glyoxalase I, and causes the accumulation of methylglyoxal followed by cell-growth inhibition. Mol Biol Rep 49, 10499–10507 (2022). https://doi.org/10.1007/s11033-022-07929-6

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