The involvement of dihydropyrazine-induced gene damage in diabetic complication

二氢吡嗪类化合物（DHP）是由非酶糖化作用形成的，已知在体内外发挥各种作用。本研究以2，3-二氢-5，6-二甲基吡嗪（DHP-1）、2，3-二氢-2，5，6-三甲基吡嗪（DHP-2）和3-二氢-2，2，5，6-四甲基吡嗪（DHP-3）为模型化合物，研究了DHP对人肝癌HepG 2细胞的作用。 所有测试的化合物都对HepG 2细胞具有细胞毒性活性，并且在最高浓度下显著。DHP-3的细胞毒性最强。此外，DHP-3暴露后，血红素氧合酶-1和谷氨酸半胱氨酸连接酶催化亚基mRNA的显着增加。糖尿病患者血清DHPs浓度较非糖尿病患者明显升高。这些结果表明，氧化应激激活的Nrf 2-ARE信号通路部分参与了DHP对哺乳动物细胞的作用。

Dihydropyrazines (DHPs), formed by nonenzymatic glycation, are known to exert various effects in vitro and in vivo. In this study, we investigated the effects of DHP on human hepatoma HepG2 cells using 2,3-dihydro-5,6-dimethylpyrazine (DHP-1), 2,3-dihydro-2,5,6-trimethylpyrazine (DHP-2), and 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3) as model compounds. All of the tested compounds exerted cytotoxic activity against HepG2 cells, and significantly so at the highest concentration. DHP-3 was the most cytotoxic drug. Additionally, DHP-3 exposure showed the significant increase of heme oxygenase-1 and glutamate cysteine ligase catalytic subunit mRNA after exposure. The serum concentration of DHPs in diabetic patient showed significant increase compared with that in non-diabetic patient. Therefore, These results suggested that the Nrf2-ARE signal pathway activated by oxidative stress is in part involved in the effect of DHP on mammalian cells.