Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Kobe, Hyogo 651-2180, Japan.
Int J Oncol. 2013 Mar;42(3):793-802. doi: 10.3892/ijo.2013.1771. Epub 2013 Jan 15.
Vitamin Ks (VKs) are fat-soluble quinone compounds known to have various bioactivities. This review describes the inflammatory effects of VKs and their related quinone derivatives based on DNA polymerase (pol) inhibition. VK3, but not VK1 or VK2 (=MK-4), inhibited the activity of human pol γ, which is the DNA replicative pol in mitochondria. Of the intermediate compounds between VK2 and VK3 (namely MK-3, MK-2 and MK-1), 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. Among the VK3 based quinone derivatives, such as 1,4-naphthoquinone (NQ), 2-dimethyl-1,4-naphthoquinone (1,2-dimethyl-NQ), 1,4-benzoquinone (BQ), 9,10-anthraquinone (AQ) and 5,12-naphthacenequinone (NCQ), NQ was the strongest inhibitor of mammalian pols α and λ, in particular, DNA repair-related pol λ. Among the all compounds tested, NQ displayed the strongest suppression of tumor necrosis factor (TNF)-α production induced by lipopolysaccharide (LPS) in a cell culture system using RAW264.7 mouse macrophages. NQ also suppressed the expression of pol λ protein in these cells, after LPS-treated RAW264.7 cells were stimulated to induce pol λ expression. In an in vivo mouse model of LPS-evoked acute inflammation, intraperitoneal injection of NQ into mice suppressed TNF-α production in peritoneal macrophages and serum. In an in vivo colitis mouse model induced using dextran sulfate sodium (DSS), NQ markedly suppressed DSS-evoked colitis. The promising anti-inflammatory candidates based on the inhibition of DNA repair-related pols, such as pol λ, by VKs quinone derivatives, such as NQ, are discussed.
维生素 Ks（VKs）是脂溶性醌类化合物，已知具有多种生物活性。本综述根据 DNA 聚合酶（pol）抑制作用描述了 VKs 及其相关醌衍生物的炎症作用。VK3 但不是 VK1 或 VK2（=MK-4）抑制了人 pol γ 的活性，pol γ 是线粒体中的 DNA 复制 pol。在 VK2 和 VK3 之间的中间化合物（即 MK-3、MK-2 和 MK-1）中，MK-2 是哺乳动物 pols α、κ 和 λ 的最强抑制剂，它们分别属于 pols 的 B-、Y-和 X-家族。在基于 VK3 的醌衍生物中，如 1,4-萘醌（NQ）、2-二甲基-1,4-萘醌（1,2-二甲基-NQ）、1,4-苯醌（BQ）、9,10-蒽醌（AQ）和 5,12-萘并醌（NCQ），NQ 是哺乳动物 pols α 和 λ 的最强抑制剂，特别是与 DNA 修复相关的 pol λ。在所测试的所有化合物中，NQ 在使用 RAW264.7 小鼠巨噬细胞的细胞培养系统中对脂多糖（LPS）诱导的肿瘤坏死因子（TNF）-α 产生的抑制作用最强。在 LPS 处理的 RAW264.7 细胞被刺激诱导 pol λ 表达后，NQ 也抑制了这些细胞中 pol λ 蛋白的表达。在 LPS 诱导的急性炎症小鼠模型中，将 NQ 腹腔内注射到小鼠体内可抑制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 DSS 诱导的结肠炎小鼠模型中，NQ 显著抑制 DSS 诱导的结肠炎。讨论了基于 VKs 醌衍生物（如 NQ）抑制与 DNA 修复相关的 pol，如 pol λ，的有希望的抗炎候选物。
