Inhibitory effects of vitamin K₃ derivatives on DNA polymerase and inflammatory activity

Int J Mol Med. 2011 Dec;28(6):937-45. doi: 10.3892/ijmm.2011.773. Epub 2011 Aug 11.


Previously, we reported that vitamin K₃ (menadione, 2-methyl-1,4-naphthoquinone) (compound 2) inhibits the activity of human mitochondrial DNA polymerase γ (pol γ). In this study, we investigated the inhibitory effects (IEs) of vitamin K3 and its derivatives, such as 1,4-naphthoquinone (compound 1) and 1,2-dimethyl-1,4-naphthoquinone (compound 3), on the activity of mammalian pols. Among compounds 1-3 (10 µM for each), compound 1 was the strongest inhibitor of mammalian pols α and λ, which belong to the B and X pol families, respectively, whereas compound 2 was the strongest inhibitor of human pol γ, a family A pol. However, these compounds did not affect the activity of human pol κ, a family Y pol. As we previously found a positive relationship between pol λ inhibition and anti-inflammatory action, we examined whether these vitamin K₃ derivatives are able to inhibit inflammatory responses. Among the three compounds tested, compound 1 caused the greatest reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ears. In addition, in a cell culture system using RAW264.7 mouse macrophages, compound 1 displayed the strongest suppression of tumor necrosis factor (TNF)-α production induced by lipopolysaccharide (LPS). In an in vivo mouse model of LPS-evoked acute inflammation, the intraperitoneal injection of compound 1 into mice suppressed TNF-α production in their peritoneal macrophages and serum. In an in vivo colitis mouse model induced using dextran sulfate sodium (DSS), the vitamin K₃ derivatives markedly suppressed DSS-evoked colitis. In conclusion, this study has identified several vitamin K₃ derivatives, such as compound 1, that are promising anti-inflammatory candidates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Colitis / chemically induced
  • Colitis / drug therapy*
  • Colitis / enzymology
  • DNA-Directed DNA Polymerase / metabolism
  • Dextran Sulfate / adverse effects
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Humans
  • Inflammation / chemically induced
  • Inflammation / drug therapy*
  • Inflammation / enzymology
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / metabolism
  • Lipopolysaccharides / adverse effects
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Naphthoquinones / pharmacology*
  • Naphthoquinones / therapeutic use
  • Nucleic Acid Synthesis Inhibitors*
  • Tetradecanoylphorbol Acetate / adverse effects
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism
  • Vitamin K 3 / pharmacology*
  • Vitamin K 3 / therapeutic use


  • Anti-Inflammatory Agents
  • Enzyme Inhibitors
  • Isoenzymes
  • Lipopolysaccharides
  • Naphthoquinones
  • Nucleic Acid Synthesis Inhibitors
  • Tumor Necrosis Factor-alpha
  • Vitamin K 3
  • Dextran Sulfate
  • DNA-Directed DNA Polymerase
  • Tetradecanoylphorbol Acetate
  • 1,4-naphthoquinone