title: Inhibitory effects of vitamin K₃ derivatives on DNA polymerase and inflammatory activity.
abstract: 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.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine,                     Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Hyogo, Japan.
authors.forename: Aoganghua
authors.initials: A
authors.lastname: Aoganghua
authors.forename: Shin
authors.initials: S
authors.lastname: Nishiumi
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nishida
authors.forename: Kouji
authors.initials: K
authors.lastname: Kuramochi
authors.forename: Kazunori
authors.initials: K
authors.lastname: Tsubaki
authors.forename: Midori
authors.initials: M
authors.lastname: Hirai
authors.forename: Shinwa
authors.initials: S
authors.lastname: Tanaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Azuma
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mizushina
authors.forename: Masaru
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D016264:Dextran Sulfate / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009285:Naphthoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D019384:Nucleic Acid Synthesis Inhibitors; D013755:Tetradecanoylphorbol Acetate / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D024483:Vitamin K 3 / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009285:Naphthoquinones; D019384:Nucleic Acid Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D024483:Vitamin K 3; D016264:Dextran Sulfate; D004259:DNA-Directed DNA Polymerase; D013755:Tetradecanoylphorbol Acetate; C035342:1,4-naphthoquinone