Effects of Quinone Derivatives, such as 1,4-Naphthoquinone, on DNA Polymerase Inhibition and Anti-Inflammatory Action
Effects of Quinone Derivatives, such as 1,4-Naphthoquinone, on DNA Polymerase Inhibition and Anti-Inflammatory Action
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DOI：
10.2174/157340611794072742
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发表时间：
2011-01-01
影响因子：
2.3
通讯作者：
Yoshida, Masaru
中科院分区：
文献类型：
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作者：
Kobayashi, Kazuki;Nishiumi, Shin;Yoshida, Masaru
此前，我们曾报道过维生素K-3具有抑制人DNA聚合酶-γ活性的作用，维生素K-3中含有一种苯醌成分。在本研究中，我们研究了4种苯醌类化合物(1，4-苯醌(BQ)、1，4-萘酚(NQ)、9，10-蒽醌(AQ)和5，12-萘醌(NCQ))对哺乳动物POL活性的抑制作用。BQ和NQ对所有Polsα、β、Gamma、Delta、epsilon和lambda的活性均有较强的抑制作用，且NQ对POL的抑制作用强于BQ。因为我们之前发现了波兰达抑制和抗炎作用之间的正相关关系，所以我们研究了这些苯醌衍生物是否可以抑制炎症反应。BQ和NQ能显著减轻12-O-十四酰佛波醇-13-乙酸酯(TPA)所致的小鼠耳部急性炎症反应，而AQ和NCQ则不能。在小鼠巨噬细胞培养体系中，对脂多糖诱导的肿瘤坏死因子-α产生的抑制作用最强的是NQ。此外，还发现NQ可抑制核因子-kappaB的作用。在内毒素诱导的小鼠急性炎症模型中，BQ和NQ可抑制血清中肿瘤坏死因子-α的产生。NQ的这些抗炎反应比BQ更强。总而言之，这项研究已经确定了几种苯醌衍生物，如NQ，它们是有希望的抗炎候选药物。
Previously, we reported that vitamin K-3, which consists of a quinone component, inhibits the activity of human DNA polymerase gamma (pol gamma). In this study, we investigated the inhibitory effects of 4 quinone derivatives (1,4-benzoquinone (BQ), 1,4-naphthoquinone (NQ), 9,10-anthraquinone (AQ) and 5,12-naphthacenequinone (NCQ)) on the activity of mammalian pols. BQ and NQ potently inhibited the activity of all the pol species: pols alpha, beta, gamma, delta, epsilon and lambda, and NQ was a stronger pol inhibitor than BQ. Because we previously found a positive relationship between pol lambda inhibition and anti-inflammatory action, we examined whether these quinone derivatives could inhibit inflammatory responses. BQ and NQ caused a marked reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ear, although AQ and NCQ did not. In a cell culture system using mouse macrophages, NQ displayed the strongest suppression in the production of tumor necrosis factor (TNF)-alpha induced by lipopolysaccharide (LPS) among the quinone derivatives tested. Moreover, NQ was found to inhibit the action of nuclear factor (NF)-kappa B. In an in vivo mouse model of LPS-evoked acute inflammation, intraperitoneal injection of BQ and NQ to mice led to suppression of TNF-alpha production in serum. These anti-inflammatory responses of NQ were more potent than those of BQ. In conclusion, this study has identified several quinone derivatives, such as NQ, that are promising anti-inflammatory candidates.