Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Hyogo, Japan.
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.
先前，我们报道了维生素 K₃（甲萘醌，2-甲基-1,4-萘醌）（化合物 2）抑制人类线粒体 DNA 聚合酶 γ（pol γ）的活性。在这项研究中，我们研究了维生素 K₃及其衍生物，如 1,4-萘醌（化合物 1）和 1,2-二甲基-1,4-萘醌（化合物 3），对哺乳动物 pols 活性的抑制作用（IEs）。在化合物 1-3（每种 10 μM）中，化合物 1 是属于 B 和 X pol 家族的哺乳动物 pols α 和 λ 的最强抑制剂，而化合物 2 是家族 A pol 人类 pol γ 的最强抑制剂。然而，这些化合物不影响家族 Y pol 人类 pol κ 的活性。由于我们先前发现 pol λ 抑制与抗炎作用之间存在正相关，因此我们研究了这些维生素 K₃ 衍生物是否能够抑制炎症反应。在所测试的三种化合物中，化合物 1 导致在小鼠耳朵中 12-O-十四烷酰佛波醇-13-乙酸酯（TPA）诱导的急性炎症中减少的程度最大。此外，在使用 RAW264.7 小鼠巨噬细胞的细胞培养系统中，化合物 1 对脂多糖（LPS）诱导的肿瘤坏死因子（TNF）-α产生的抑制作用最强。在 LPS 诱发的急性炎症的体内小鼠模型中，将化合物 1 腹腔内注射到小鼠中可抑制其腹腔巨噬细胞和血清中 TNF-α的产生。在使用葡聚糖硫酸钠（DSS）诱导的体内结肠炎小鼠模型中，维生素 K₃ 衍生物显著抑制 DSS 诱导的结肠炎。总之，这项研究鉴定了几种维生素 K₃ 衍生物，如化合物 1，它们是有前途的抗炎候选物。
