Glutathione depression by dihydropyrazine derivative

Takechi, Seiji; Ito, Shigeru; Kashige, Nobuhiro; Ishida, Tatsuro; Yamaguchi, Tadatoshi

doi:10.2131/jts.36.231

Cited by 8 publications

(9 citation statements)

References 23 publications

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“…Despite concerns surrounding the effects of DHPs on human health, there is very little evidence in the literature regarding a causal relationship between DHP and disease. We previously reported that DHP causes greater growth inhibition in GSH-deficient bacteria than it does in GSH-sufficient bacteria (Takechi et al, 2011), and we also observed a significant decrease in the ratio of intracellular reduced glutathione and oxidized glutathione (GSH/GSSG) in DHP-exposed cultured cell (Ishida et al, 2012). In the current study, we have identified novel DHP-GSH adducts from the reaction products of DHP with GSH.…”

Section: Introductionsupporting

confidence: 53%

“…Given that GSH is converted to GSSG following its reaction with ROS, and GSH depletion results in elevated cytotoxicity (Mitchell and Russo, 1987). In our previous study, DHP caused growth inhibition of GSH-deficient bacteria (Takechi et al, 2011), and DHP also led to a decrease in the ratio of intracellular GSH/GSSG in cultured cells (Ishida et al, 2012). In addition, the exposure of cells to DHP led to the induction of antioxidant gene expression via the activation of the Nrf2-ARE pathway (Ishida et al, 2014).…”

Section: Resultsmentioning

confidence: 86%

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Identification of dihydropyrazine-glutathione adducts

et al. 2015

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-Dihydropyrazines (DHPs) are glycation intermediates generated both in vivo and in food. DHPs can lead to the formation of a variety of different radical species, which can lead to DNA damage and enzyme inhibition. In addition, the presence of DHPs can lead to a decrease in cellular glutathione (GSH) levels, and induce the expression of antioxidant genes. In this study, the products resulting from the reaction of DHP with GSH have been analyzed in detail, with some of the products being separated by reversed-phase HPLC. The structures of the isolated DHP-GSH adducts were determined by FAB-MS and NMR analyses. These data suggested that the reaction of DHP with a thiol moiety could be involved in oxidative stress, because an increase in the amount of DHP-GSH adducts would result in a decrease in the cellular GSH levels.

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Section: Introductionsupporting

confidence: 53%

Section: Resultsmentioning

confidence: 86%

Identification of dihydropyrazine-glutathione adducts

et al. 2015

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“…The genotoxic 1,4,29) and cytotoxic 11,28,30) potentials of DHPs have been demonstrated previously. As stated earlier, the biological effects of DHPs are due to DHPs' dual capacity for high chemical reactivity and radical generation activity.…”

Section: +mentioning

confidence: 59%

Generation of Radical Species from Dihydropyrazines Having DNA Strand-Breakage Activity and Other Characteristics

Yamaguchi

Matsumoto

Masumizu

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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The various biological activity of dihydropyrazines(DHPs)due to the radical generation potency has been described in previous papers. Detailed data about radical species generating be mentioned here. The electron spin resonance (ESR) spin-trapping technique revealed that DHPs generate free radical species such as · OH, · OOH, · CHR 2 and · CR 3 . Oxygen radicals and two carbon-centered radicals were detected as adducts of the spin traps DMPO and DBNBS, respectively. All the 5,5-dimethyl-1-pyrroline-N-oxide (DMPO)-and 3,5-dibromo-4-nitrosobenzenesulfonate (DBNBS)-adducts of compounds DHP-1-8 exhibited approximately the same signal patterns, with various levels of intensity depending on the substituent of the dihydropyrazine ring. The ESR signal intensity of DHPs also increased remarkably upon addition of Cu 2 , resulting that the effects of DHPs were enhanced.

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“…In addition, cyclohexyl-DHP, which was designed according to our hypothesis of a relationship between the chemical structure of DHP derivatives and their DNA strand-cleaving activity (Maruoka et al, 2005), was shown to possess stronger DNA strand-cleaving activity than Me-DHP or Ph-DHP . More recently, it has been reported that the reaction of some Me-DHPs or cyclohexyl-DHP with GSH is a potential mechanism of bacterial growth inhibition (Takechi et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Possible involvement of glutathione balance disruption in dihydropyrazine-induced cytotoxicity on human hepatoma HepG2 cells

2012

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-Dihydropyrazines (DHPs), formed by nonenzymatic glycation, are known to exert various effects in vitro and in vivo, such as generation of radical species, DNA strand breakage, enzyme inhibition, and inhibition of bacterial growth. However, their effects on mammalian cells remain elusive.To address this issue, we investigated the effects of a range of DHP concentrations 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 in the range of 10 μM-1 mM, and significantly so at the highest concentration. DHP-3 was the most effective drug, and it also caused a significant decrease in the ratio of intracellular reduced and oxidized glutathione (GSH/GSSG). In addition, the cytotoxic effect of DHP-3, but not DHP-1 and DHP-2, was enhanced by the inhibition of GSH biosynthesis using 100 μM L-buthionine-(S,R)-sulfoximine (BSO). From these results, it is suggested that the mechanisms of cytotoxicity exerted by DHP-3 are distinct from those exerted DHP-1 and DHP-2. In addition, it is possible that the disruption of intracellular glutathione balance induced by DHP-3 is related to its effect on HepG2 cells.

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Glutathione depression by dihydropyrazine derivative

Cited by 8 publications

References 23 publications

Identification of dihydropyrazine-glutathione adducts

Identification of dihydropyrazine-glutathione adducts

Generation of Radical Species from Dihydropyrazines Having DNA Strand-Breakage Activity and Other Characteristics

Possible involvement of glutathione balance disruption in dihydropyrazine-induced cytotoxicity on human hepatoma HepG2 cells

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