S-adenosylhomocysteine enhances hydrogen peroxide-induced DNA damage by inhibition of DNA repair in two cell lines.
It has been proposed that hyperhomocysteinemia may exert its pathogenic effects largely through metabolic accumulation of S-adenosylhomocysteine (SAH), a strong noncompetitive inhibitor of most methyltransferases. Here, we investigated the effects of SAH on H(2)O(2)-induced cellular DNA damage in comparison with the effects of homocysteine (Hcy) in a mouse endothelial cell line and a human intestinal cell line. Cells were preincubated for 2 h with H(2)O(2) (20 microM) followed by incubation with SAH or Hcy for 3 h. DNA strand breakage was determined using comet assay and DNA repair capacity determined using the same assay over time at 1, 2, and 3 h during SAH incubation. In both types of cells, SAH at 0.25-2 microM strongly and dose dependently enhanced H(2)O(2)-dependent DNA damage and inhibited DNA repair, whereas Hcy had a much weaker effect. SAH markedly increased uracil misincorporation, and this effect was also much stronger than that of Hcy. Taken together, our results show that SAH potentiates H(2)O(2)-induced DNA damage in cell cultures through impaired DNA repair capability and suggest that such effects are related to uracil misincorporation. Although the in vivo relevance of our findings is unclear, the biological significance of SAH-mediated detrimental effect, secondary to elevated intracellular Hcy, is an interesting area awaiting further exploration.
Yang
Tsai-Hsiu
TH
Department of Food Science, National Chung-Hing University, 250 Kuo-Kuang Road, Taichung, Taiwan 402, ROC.
Yang
Nae-Cherng
NC
Hu
Miao-Lin
ML
D000818:Animals; D002460:Cell Line; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D042783:Endothelial Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007422:Intestines; D051379:Mice; D012435:S-Adenosylhomocysteine / Q000494:pharmacology*; D014498:Uracil / Q000378:metabolism
D014498:Uracil; D012435:S-Adenosylhomocysteine; D006861:Hydrogen Peroxide