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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STUDY: Testing reveals scores of substances in study volunteers

JOURNAL: Environmental Working Group

AUTHORS: Jane Houlihan

ABSTRACT: When scientists sampled Andrea Martin’s blood and urine to see what toxins she’d picked up from the world around her, she got a surprise. “I had 95 chemical contaminants in my little body. And it was very mind blowing,” said Martin. The test results indicate that we all pick up tiny amounts of an astounding number of chemicals that are known to be dangerous in larger doses.

COMMENTARY: Martin and eight others were tested by Mt. Sinai School of Medicine in New York and an advocacy organization called the Environmental Working Group.

On average, the nine participants had traces of 53 chemicals known to cause cancer in human or animal tests. In addition, they had an average of 62 chemicals toxic to the brain or nervous system, plus 55 associated with birth defects.

The scientists did not find any single substance in amounts the government describes as unhealthy, but said the sheer number of chemicals was unnerving, especially given the uncertainty about the health effects of trace amounts.

"This is irrefutable proof that humans carry in their bodies scores of industrial contaminants, most of which didn’t exist 75 years ago,” said Jane Houlihan, co-author of the study.

Scientists have found chemicals called pthalates, which are known to cause birth defects in animals, in many personal care items like makeup, hairspray, soap and also plastic food wrap.

Other chemicals found in the participants’ bodies target the nervous system, including: Acetone in nail polish synthetic fragrances in perfume and soap, poisons in weed killers and bug sprays, perchloral ethyline in dry cleaners, zylene in paint which can also cause organ damage.

For those intent on avoiding even traces of toxic chemicals, the study’s authors suggest eating organic produce, minimizing fatty foods since chemicals concentrate in body fat, minimizing the use of beauty products, avoiding stain removers and avoiding seafood known to be high in mercury.

These precautions may be more hassle than many care to deal with, but the scientists in charge of the study say it is amazing how many potentially toxic chemicals get in our bodies.