Effects of intermediates between vitamins K(2) and K(3) on mammalian DNA polymerase inhibition and anti-inflammatory activity.

Abstract

Previously, we reported that vitamin K(3) (VK(3)), but not VK(1) or VK(2) (=MK-4), inhibits the activity of human DNA polymerase γ (pol γ). In this study, we chemically synthesized three intermediate compounds between VK(2) and VK(3), namely MK-3, MK-2 and MK-1, and investigated the inhibitory effects of all five compounds on the activity of mammalian pols. Among these compounds, MK-2 was the strongest inhibitor of mammalian pols α, κ and λ, which belong to the B, Y and X families of pols, respectively; whereas VK(3) was the strongest inhibitor of human pol γ, an A-family pol. MK-2 potently inhibited the activity of all animal species of pol tested, and its inhibitory effect on pol λ activity was the strongest with an IC(50) value of 24.6 μM. However, MK-2 did not affect the activity of plant or prokaryotic pols, or that of other DNA metabolic enzymes such as primase of pol α, RNA polymerase, polynucleotide kinase or deoxyribonuclease I. Because we previously found a positive relationship between pol λ inhibition and anti-inflammatory action, we examined whether these compounds could inhibit inflammatory responses. Among the five compounds tested, MK-2 caused the greatest reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ear. In addition, in a cell culture system using mouse macrophages, MK-2 displayed the strongest suppression of the production of tumor necrosis factor (TNF)-α induced by lipopolysaccharide (LPS). Moreover, MK-2 was found to inhibit the action of nuclear factor (NF)-κB. In an in vivo mouse model of LPS-evoked acute inflammation, intraperitoneal injection of MK-2 in mice led to suppression of TNF-α production in serum. In conclusion, this study has identified VK(2) and VK(3) intermediates, such as MK-2, that are promising anti-inflammatory candidates.

• Authors: Yoshiyuki Mizushina, Jun Maeda, Yasuhiro Irino, Masayuki Nishida, Shin Nishiumi, Yasuyuki Kondo, Kazuyuki Nishio, Kouji Kuramochi, Kazunori Tsubaki, Isoko Kuriyama, Takeshi Azuma, Hiromi Yoshida, Masaru Yoshida
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 12 Issue 2 Pg. 1115-32 (Feb 10 2011) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 21541047 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• NF-kappa B
• Tumor Necrosis Factor-alpha
• Vitamin K 2
• Vitamin K 3
• DNA Polymerase gamma
• DNA-Directed DNA Polymerase

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Cattle
• Cell Line
• DNA Polymerase gamma
• DNA-Directed DNA Polymerase (metabolism)
• Humans
• Macrophages (drug effects, metabolism)
• Mice
• NF-kappa B (metabolism)
• Otitis (drug therapy)
• Species Specificity
• Tumor Necrosis Factor-alpha (metabolism)
• Vitamin K 2 (analogs & derivatives, pharmacology, therapeutic use)
• Vitamin K 3 (analogs & derivatives, pharmacology, therapeutic use)