Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon
Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon
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DOI：
10.1016/j.jnutbio.2007.08.002
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发表时间：
2008-09-01
影响因子：
5.6
通讯作者：
Schrenk, Dieter
中科院分区：
文献类型：
--
作者：
Waldecker, Markus;Kautenburger, Tanja;Schrenk, Dieter
结直肠癌是西方世界癌症死亡率最高的原因。营养和微生物菌群被认为对结直肠癌的风险有显著影响，丁酸盐和其他短链脂肪酸（SCFAs）的形成可能在结肠微生物发酵的化学预防产物中发挥重要作用。在这项研究中，我们以叔丁基羰基赖氨酸（乙酰化）-4-氨基-7-甲基香豆素（Boc-Lys(Ac)-AMC）为底物，研究了肠道降解果蔬油中多酚成分（HDAC）活性过程中形成的丁酸盐、其他SCFA以及一些酚类SCFA和反式肉桂酸衍生物对结肠癌细胞培养核提取物中组蛋白脱乙酰酶（HDAC）活性的影响。抑制HDAC活性，例如通过丁酸盐，与抑制恶性转化和刺激癌前结肠细胞凋亡有关。在HT-29人结肠癌细胞的核提取物中，丁酸盐被发现是最有效的HDAC抑制剂（IC50=0.09 mM），而其他SCFAs如丙酸盐的抑制作用较弱。在同一实验中，对香豆酸（IC50=0.19 mM）、3-（4- oh -苯基）-丙酸（IC50()=0.62 mM）和咖啡酸（IC50=0.85 mM）是测试的多酚代谢物中最有效的HDAC抑制剂。有趣的是，在基于HeLa Mad 38的全细胞报告基因试验中，丁酸盐也是最有效的HDAC抑制剂，而所有多酚代谢物和所有其他SCFAs测试的效力要小得多；有些完全不活跃。研究结果表明，丁酸盐在结肠中作为内源性HDAC抑制剂发挥着突出的作用，而结肠中存在的其他scfa和HDAC抑制多酚代谢物似乎发挥的作用要小得多，这可能是因为它们的水平有限，细胞毒性明显和/或细胞内可用性有限。(c) 2008爱思唯尔公司版权所有。
Colorectal cancer is the most abundant cause of cancer mortality in the Western world. Nutrition and the microbial flora are considered to have a marked influence on the risk of colorectal cancer, the formation of butyrate and other short-chain fatty acids (SCFAs) possibly playing a major role as chemopreventive products of microbial fermentation in the colon. In this Study, we investigated the effects of butyrate, other SCFAs, and of a number of phenolic SCFA and trans-cinnamic acid derivatives formed during the intestinal degradation of polyphenolic Constituents of Fruits and vegetables oil global histone deacetylase (HDAC) activity in nuclear extracts from colon carcinoma cell Cultures using tert-butoxycarbonyl-lysine (acetylated)-4-amino-7-methylcoumarin (Boc-Lys(Ac)-AMC) as Substrate. Inhibition of HDAC activity, e.g., by butyrate, is related to a Suppression of malignant transformation and a stimulation of apoptosis of precancerous colonic cells. In nuclear extracts from HT-29 human colon carcinoma cells, butyrate was found to be the most potent HDAC inhibitor (IC50=0.09 mM), while other SCFAs Such as propionate were less potent. In the same assay, p-coumaric acid (IC50=0.19 mM), 3-(4-OH-phenyl)-propionate (IC50()=0.62 mM) and caffeic acid (IC50=0.85 mM) were the most potent HDAC inhibitors among the polyphenol metabolites tested. Interestingly, butyrate was also the most potent HDAC inhibitor in a whole-cell HeLa Mad 38-based reporter gene assay, while all polyphenol metabolites and all other SCFAs tested were much less potent; some were completely, inactive. The findings Suggest that butyrate plays an outstanding role as endogenous HDAC inhibitor in the colon, and that other SCFAs and HDAC-inhibitory polyphenol metabolites present in the colon seem to play a much smaller role, probably because of their limited levels, their marked cytotoxicity and/or their limited intracellular availability. (c) 2008 Elsevier Inc. All rights reserved.