The involvement of dihydropyrazine-induced gene damage in diabetic complication

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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.