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Effects of Intermediates between Vitamins K2 and K3 on Mammalian DNA Polymerase Inhibition and Anti-Inflammatory Activity
Laboratory of Food & Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan
Cooperative Research Center of Life Sciences, Kobe-Gakuin University, Chuo-ku, Kobe, Hyogo 650-8586, Japan
Division of Gastroenterology, Department of Internal Medicine, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe, Hyogo 650-0017, Japan
The Integrated Center for Mass Spectrometry, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe, Hyogo 650-0017, Japan
Graduate School of Life and Environmental Science, Kyoto Prefectural University, Sakyo-ku, Kyoto 606-8522, Japan
Division of Metabolomics Research, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe, Hyogo 650-0017, Japan
* Authors to whom correspondence should be addressed.
Received: 13 December 2010; in revised form: 21 January 2011 / Accepted: 8 February 2011 / Published: 10 February 2011
Abstract: Previously, we reported that vitamin K3 (VK3), but not VK1 or VK2 (=MK-4), inhibits the activity of human DNA polymerase γ (pol γ). In this study, we chemically synthesized three intermediate compounds between VK2 and VK3, 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 VK3 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 IC50 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 VK2 and VK3 intermediates, such as MK-2, that are promising anti-inflammatory candidates.
Keywords: vitamin K; MK-2; DNA polymerase λ; enzyme inhibitor; anti-inflammation
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Mizushina, Y.; Maeda, J.; Irino, Y.; Nishida, M.; Nishiumi, S.; Kondo, Y.; Nishio, K.; Kuramochi, K.; Tsubaki, K.; Kuriyama, I.; Azuma, T.; Yoshida, H.; Yoshida, M. Effects of Intermediates between Vitamins K2 and K3 on Mammalian DNA Polymerase Inhibition and Anti-Inflammatory Activity. Int. J. Mol. Sci. 2011, 12, 1115-1132.
Mizushina Y, Maeda J, Irino Y, Nishida M, Nishiumi S, Kondo Y, Nishio K, Kuramochi K, Tsubaki K, Kuriyama I, Azuma T, Yoshida H, Yoshida M. Effects of Intermediates between Vitamins K2 and K3 on Mammalian DNA Polymerase Inhibition and Anti-Inflammatory Activity. International Journal of Molecular Sciences. 2011; 12(2):1115-1132.
Mizushina, Yoshiyuki; Maeda, Jun; Irino, Yasuhiro; Nishida, Masayuki; Nishiumi, Shin; Kondo, Yasuyuki; Nishio, Kazuyuki; Kuramochi, Kouji; Tsubaki, Kazunori; Kuriyama, Isoko; Azuma, Takeshi; Yoshida, Hiromi; Yoshida, Masaru. 2011. "Effects of Intermediates between Vitamins K2 and K3 on Mammalian DNA Polymerase Inhibition and Anti-Inflammatory Activity." Int. J. Mol. Sci. 12, no. 2: 1115-1132.