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Study: Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon.
Authors: Waldecker M, Kautenburger T, Daumann H, Busch C, Schrenk D.
Journal: Food Chemistry and Environmental Toxicology, University of Kaiserslautern, D-67663 Kaiserslautern, Germany.
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.
Abstract: This study investigated the effects of a number of short chain fatty acids, to include butyrate, as well as a number of phenolic SCFA and trans-cinnamic acid derivatives formed during the intestinal degradation of polyphenolic constituents of fruits and vegetables on global histone deacetylase (HDAC) activity in nuclear extracts from colon carcinoma cell cultures. 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 (IC(50)=0.09 mM), while other SCFAs such as propionate were less potent. In the same assay, p-coumaric acid (IC(50)=0.19 mM), 3-(4-OH-phenyl)-propionate (IC(50)=0.62 mM) and caffeic acid (IC(50)=0.85 mM) were the most potent HDAC inhibitors among the polyphenol metabolites tested.
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.
Commentary: Butyric acid is notably found in rancid butter, aged cheeses, and has an unpleasant odor and acrid taste, with a sweetish aftertaste. The glyceride of butyric acid makes up 3% to 4% of butter. When butter goes rancid, butyric acid is liberated from the glyceride by hydrolysis leading to the unpleasant odor. It is an important member of the fatty acid sub-group called short chain fatty acids.
Butyric acid supports the health and healing of cells in the small and large intestine. Many research studies, like the one above, have demonstrated that butyric acid impedes the ability of cancer cells to proliferate in the colon, and therefore is protective of colon cancer. Butyric acid changes the structure of chromatin through its effects on posttranslational modifications, key modifications being acetylation and phosphorylation of the nuclear histones. These enzymes remove an acetyl group from histones, which allows histones to bind DNA and inhibit gene transcription. HDAC inhibitors disrupt the cell cycle and/or induce apoptosis via de-repression of genes such as P21 and BAX, and cancer cells appear to be more sensitive than non-transformed cells HDAC inhibitory compounds.
Butyric acid can also modify the differentiation state of cells, and in the case of cancerous colonic cells overcomes their resistance to normal programmed death. Thus, the activities of this fermentation product of dietary fiber may contribute substantially to the decreased incidence of bowel cancer that has been associated with fiber intake. Adverse butyrate effects occur in normal and neoplastic colonic cells. In normal cells, butyrate induces proliferation at the crypt base, while inhibiting proliferation at the crypt surface. In neoplastic cells, butyrate inhibits DNA synthesis and arrests cell growth in the G1 phase of the cell cycle.
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