Oxidative Stress Induced by a Dihydropyrazine Derivative

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The Maillard reaction contributes to the complications of diabetes and normal aging. Dihydropyrazines (DHPs), which are produced during the Maillard reaction, generate radicals and possess DNA strand-cleaving activities in vitro. In the present study, we evaluated the genotoxic and cytotoxic potentials of a DHP derivative, cyclohexyl-DHP, which is obtained as a mixture of two isomers, 2,3,5,6,7,8-hexahydroquinoxaline (endo-type) and 1,2,3,5,6,7-hexahydroquinoxaline (exo-type), fused with a cyclohexyl ring. Cyclohexyl-DHP caused DNA strand breaks in plasmid pUC18, especially in the presence of Cu2+. By using Escherichia coli mutant strains, we observed that cyclohexyl-DHP exposure strongly reduced the survival rate of a cytosolic sodium dodecyl sulfate (SOD)-deficient strain (sodA sodB), significantly reduced the survival rates of DNA repair-deficient strains (recA and uvrB) and mildly reduced the survival rate of a catalase-deficient strain (katE katG) compared with the survival rate of the wild-type strain. Addition of Cu2+ enhanced the cell killing ability of cyclohexyl-DHP. The frequency of mutations induced by cyclohexyl-DHP increased dose-dependently in the sodA sodB strain. Assays with the highly water-soluble tetrazolium salt WST-1 revealed that cyclohexyl-DHP strongly generated superoxide anions. Moreover, cyclohexyl-DHP elevated the protein carbonyl levels in E. coli. These findings indicate that cyclohexyl-DHP could potentially generate superoxide anions, and cause not only breakage of chromosomal DNA leading to mutagenic lesions but also induce damage to cellular proteins.

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