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PubMed1978

The effect of sodium butyrate on histone modification.

The hyperacetylation of histones due to treatment of cultured cells with sodium butyrate has been studied. The hyperacetylation is due to inhibition of histone deacetylase. Other short chain fatty acids including acetic, isobutyric and propionic acid also produce increased modification. Histone H4 already deposited on the chromosome can be rapidly acetylated to the extent of about 70%. That 80% of histone H4 is acetylated after a 24 hr exposure to butyrate is due to the fact that incoming H4 histone is 100% acetylated and does not return to the parental unmodified form in the presence of butyrate.

Acetates↗
PubMed1984

Absorption and metabolism of butyric acid in rabbit hind gut.

Butyrate absorption in the large intestine of the rabbit was evaluated by the variation of concentrations in the bowel, the arterio-venous plasma and the intestinal loops. The metabolic transformations were studied with (3-4 C14) butyrate. The caeco-colonic epithelium oxidized negligible quantities of butyrate to ketone bodies and other metabolic pathways were found. These pathways were of different intensity according to the region of the gut and both phases of the excretory cycle. A portion, which may be large, was metabolized in the caeco-colonic wall and in the liver where radioactivity was found in free amino acids, carboxylic acids and sugars. The oxidation to CO2 in TCA cycle yields energy for metabolic activities. This study of metabolism takes account of the endoflora participation.

Absorption↗
PubMed1980

Early reversible nuclear alterations induced by sodium butyrate in cultured hepatoma cells.

Exposure of HTC cells to sodium butyrate caused various cellular and subcellular changes. A high proportion of the cells became elongated or spherical after 48 h. Already after 1-4 h, nucleoli appeared modified as shown by changes in the distribution of their components. Progressively, most of the cytoplasmic components were altered, suggesting an effect of butyrate on membranes. Most of the butyrate-induced modifications disappeared 1-2 days after transfer of the cells into a normal medium.

Animals↗
PubMed2004

N-[18F]fluoroethylpiperidin-4-ylmethyl butyrate: a novel radiotracer for quantifying brain butyrylcholinesterase activity by positron emission tomography.

In Alzheimer's disease, cerebral cortical butyrylcholinesterase (BChE) activity is reported to be elevated. Our aim was to develop a novel (18)F-labeled tracer for quantifying cerebral BChE activity by positron emission tomography. With in vitro screening of N-[(14)C]ethylpiperidin-3- and 4-ylmethyl esters, N-[(14)C]ethylpiperidin-4-ylmethyl butyrate was selected as a lead for (18)F-labeling, affording N-[(18)F]fluoroethylpiperidin-4-ylmethyl butyrate. The (18)F-labeled butyrate showed the required properties for in vivo BChE measurement, that is, the lipophilic nature of the authentic ester, high specificity to BChE, a moderate hydrolysis rate, and the hydrophilic nature of the metabolite.

Acetylcholinesterase↗
PubMed2006

Targeting glycosylation pathways and the cell cycle: sugar-dependent activity of butyrate-carbohydrate cancer prodrugs.

Short-chain fatty acid (SCFA)-carbohydrate hybrid molecules that target both histone deacetylation and glycosylation pathways to achieve sugar-dependent activity against cancer cells are described in this article. Specifically, n-butyrate esters of N-acetyl-D-mannosamine (But4ManNAc, 1) induced apoptosis, whereas corresponding N-acetyl-D-glucosamine (But4GlcNAc, 2), D-mannose (But5Man, 3), or glycerol (tributryin, 4) derivatives only provided transient cell cycle arrest. Western blots, reporter gene assays, and cell cycle analysis established that n-butyrate, when delivered to cells via any carbohydrate scaffold, functioned as a histone deacetylase inhibitor (HDACi), upregulated p21WAF1/Cip1 expression, and inhibited proliferation. However, only 1, a compound that primed sialic acid biosynthesis and modulated the expression of a different set of genes compared to 3, ultimately killed the cells. These results demonstrate that the biological activity of butyrate can be tuned by sugars to improve its anticancer properties.

Apoptosis↗
PubMed2005

SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter.

The identification of SLC5A8 as a tumor suppressor gene in colorectal cancer marks, for the first time, the association of a plasma membrane transporter with tumor suppressive properties. The subsequent establishment of the functional identity of SLC5A8 as a Na+-coupled transporter for short-chain monocarboxylates provides a mechanism for the tumor suppressive function of the transporter. Butyrate, a substrate for the transporter, is a histone deacetylase inhibitor and protective against colorectal cancer. This fatty acid is produced in the colonic lumen by bacterial fermentation of dietary fiber. SLC5A8 mediates the concentrative entry of butyrate from the lumen into colonocytes. Consequently, the transport function of SLC5A8 has the ability to influence the acetylation status of histones and hence gene expression in colonocytes. The ability of SLC5A8 to deliver butyrate into colonic epithelial cells most likely underlies the tumor suppressive role of this transporter.

Animals↗
PubMed2005

Effect of iron on the sensitivity of hydrogen, acetate, and butyrate metabolism to inhibition by long-chain fatty acids in vegetable-oil-enriched freshwater sediments.

Freshwater sediment microbial communities enriched by growth on vegetable oil in the presence of a substoichiometric amount of ferric hydroxide (sufficient to accept about 12% of the vegetable-oil-derived electrons) degrade vegetable oil to methane faster than similar microbial communities that develop when sediments are enriched by growth on vegetable oil in the absence of ferric hydroxide. This study examined the effects of enrichment in the presence of Fe(III) on the fatty-acid sensitivity of several important members of anaerobic triglyceride-degrading microbial communities in freshwater sediments. The fatty-acid sensitivity of three groups of microorganisms-hydrogenotrophic methanogens, acetate consumers, and hydrogen-producing acetogens-were investigated by comparing the rates of hydrogen, acetate, or butyrate consumption in the presence and absence of oleic acid. Methanogenesis from hydrogen was not affected by sediment enrichment conditions or by the presence of oleic acid, suggesting that hydrogenotrophic methanogens were insensitive to fatty acid inhibition in these sediments. Oleic acid inhibited the anaerobic degradation rates of acetate and butyrate by 38% and 63%, respectively, but enrichment in the presence of Fe(III) eliminated the fatty-acid sensitivity of acetate degradation and reduced the sensitivity of butyrate degradation by about half. These results suggest that iron-reducing bacteria may provide an alternative pathway through which vegetable oil can be converted to methane in anaerobic freshwater sediments.

Acetates↗
PubMed2003

Apoptosis induced by butyrate is independent of Jak/STAT signaling in a fibrosarcoma cell line.

The aim of this study was to evaluate the participation of the Jak-1 and STAT-1 proteins in sodium butyrate-induced apoptosis in 2C4 cells derived from human fibrosarcoma. Making use of Jak-1 or STAT-1 deficient cell lines, we demonstrated that the apoptotic process induced by butyrate is independent of the presence of these proteins. In addition, this work showed that, although the constitutive expression of pro-caspases-2 and -3 is reduced in STAT-1 cells, the activity of caspase-3 is preserved in both Jak-1 and STAT-1 deficient cells and is similar to that seen in 2C4 parental cells. In conclusion, we demonstrated that the absence of functionally active Jak-1 or STAT-1 protein directly affects the TNF-alpha-induced apoptosis, but does not alter the sodium butyrate-induced apoptosis in cells derived from human fibrosarcoma.

Apoptosis↗
PubMed2002

Enhancement of NGF- and cholera toxin-induced neurite outgrowth by butyrate in PC12 cells.

It has been shown that sodium butyrate (NaBu) does not elicit neurite outgrowth of PC12, one of the most widely used cell lines as a model of neuronal differentiation. In this study, the effects of NaBu on nerve growth factor (NGF)- and cholera toxin-induced neurite outgrowth in PC12 cells were examined. NaBu dose-dependently enhanced neurite formation induced by both agents. The maximum responses obtained at 0.5 mM NaBu were nearly twice those of the inducers alone. Propionate and valerate were also effective, but acetate and caproate were ineffective. Among the butyrate analogs with a moiety of three to five carbon atoms tested, isobutyrate, isovalerate, vinylacetate and 3-chloropropionate enhanced neurite outgrowth promoted by both inducers. However, neither alpha-, beta-, and gamma-aminobutyrates nor alpha-, beta-, and gamma-hydroxybutyrates were effective. All of the effective short-chain fatty acids and their analogs increased the level of histone acetylation, while ineffective ones did not. Furthermore, Helminthosporium carbonum toxin (HC toxin), a structurally dissimilar inhibitor of histone deacetylase, mimicked the effect of butyrate. These results suggest that NaBu enhances neurite outgrowth induced by NGF and cholera toxin in PC12 cells through a mechanism involving an increase in the level of histone acetylation.

Acetylation↗
PubMed1999

Induction of catecholamine synthesis in human neuroblastoma cells by replication inhibitors and sodium butyrate.

Various inhibitors of DNA synthesis induced neurite extension in human neuroblastoma cells. In order to clarify morphology-function relationship in differentiation of neuroblastoma cells, the effect of the replication inhibitors on inducibility of catecholamine synthesis was examined. The reagents alone did not affect production of dopamine and noradrenaline, but joint administration of each inhibitor and sodium butyrate considerably promoted the catecholamine synthesis, without additional change in neurite profile. Although inactive in neurite extension, sodium butyrate was moderately active in catecholamine production. The promoting effect of thymidine (or hydroxyurea) and sodium butyrate was repealed by alpha-amanitin, actinomycin D or cycloheximide.

Amanitins↗
PubMed2001

Direct block of the cystic fibrosis transmembrane conductance regulator Cl(-) channel by butyrate and phenylbutyrate.

Chloride permeation through the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel is inhibited by a broad range of intracellular organic anions. Here it is shown, using patch clamp recording from CFTR-transfected mammalian cell lines, that the fatty acids butyrate and 4-phenylbutyrate cause a voltage-dependent block of CFTR Cl(-) currents when applied to the cytoplasmic face of membrane patches, with apparent K(d)s (at 0 mV) of 29.6 mM for butyrate and 6.6 mM for 4-phenylbutyrate. At the single channel level, both these fatty acids caused an apparent reduction in CFTR current amplitude, suggesting a kinetically fast blocking mechanism. The concentration-dependence of block suggests that CFTR-mediated Cl(-) currents in vivo may be affected by both 4-phenylbutyrate used in the treatment of various diseases, including cystic fibrosis, and by butyrate produced endogenously within the colonic lumen.

Animals↗
PubMed2000

Augmentation of urea-synthetic capacity by inhibition of nitric oxide synthesis in butyrate-induced differentiated human hepatocytes.

We have recently developed an in vitro differentiation model of immortalized non-transformed human hepatocytes using butyrate, and observed the induction of inducible NO synthase (iNOS). In this study, we analyzed the effect of NO on the urea-synthetic capacity of these cells. The inhibition of iNOS during butyrate treatment significantly increased the urea-synthetic capacity as compared to that of butyrate treatment alone, possibly through the further induction of ornithine transcarbamylase expression. Therefore, the inhibition of NO production might be useful for obtaining more differentiated hepatocytes in the process of in vitro induction of hepatocyte-specific differentiation.

Argininosuccinate Synthase↗
PubMedDate not supplied

Apoptosis after butyrate-induced differentiation in retinoblastoma cell line Y-79.

PURPOSE: To study the fate of Y-79 human retinoblastoma cells after induction of differentiation. METHODS: Y-79 cells were cultured in a synthetic medium and were induced to neuronal differentiation by butyrate treatment. Neurofilaments, p53, and DNA-synthesizing nuclei labeled with 5-bromodeoxyuridine were immunostained, and apoptotic cells were labeled by in situ DNA nick end labeling (TUNEL). We combined these immunostaining and labeling methods to determine whether the cells expressed these markers at the same time. DNA fragmentation and p53 levels were also determined by electrophoresis. RESULTS: Y-79 cells proliferated in the synthetic medium. After butyrate treatment, they extended protrusions and increased neurofilament immunoreactivity. The differentiated features were striking on day 7. Thereafter, differentiated cells decreased and apoptotic cells increased. DNA synthesis was detected in the cells expressing immunoreactivity for neurofilaments or p53. At day 7, most of the cells with p53-positive nuclei were alive and neurofilament-positive. However at day 10, the p53-positive cells were apoptotic and neurofilament-positive apoptotic cells accumulated. CONCLUSIONS: We conclude that the Y-79 cells express p53 and undergo apoptosis after neuronal differentiation. There could be a p53-dependent apoptotic pathway in butyrate-induced differentiated Y-79 cells due to the inability to regulate cell cycling.

Apoptosis↗
PubMed1999

NSAIDs and butyrate sensitize a human colorectal cancer cell line to TNF-alpha and Fas ligation: the role of reactive oxygen species.

The nonsteroidal antiinflammatory drugs (NSAIDs) indomethacin and salicylic acid and the short chain fatty acid butyrate are effective colon cancer chemopreventive agents that increase reactive oxygen species (ROS) generation in colon cancer cells. Here we demonstrate that these agents sensitize the normally resistant human HT-29 colon cancer cell line to apoptosis induced by TNF-alpha or a Fas ligating antibody. The role of ROS in this sensitization is supported by the finding that direct exposure of the cells to H2O2 is sufficient for sensitization. Neither TNF-alpha nor Fas ligation alter basal or chemopreventive agent-activated ROS generation, suggesting that the death ligands and chemopreventive agents act in a complementary fashion. The dual chemopreventive agent/death ligand treatments do not increase Fas, TNF receptor 1, Bak or c-myc expression (although salicylic acid moderately induces of Fas expression). Cell death does correlate with alterations in NF-kappa B activity: the NSAIDs, butyrate and H2O2 enhance c-Rel complex formation by TNF-alpha and provide an overall enhancement of NF-kappa B activation by Fas. The antioxidant N-acetylcysteine (NAC) blocks cell death and NF-kappa B activation induced by Fas ligation, suggesting a potential role for NF-kappa B in Fas-induced apoptosis in these cells. The effects of NAC on TNF-alpha-induced cell death are more complex, with NAC being marginally protective and itself enhancing the formation of c-Rel containing complexes at higher concentrations (25 mM). The influence of NSAIDs and butyrate on ROS generation and death ligand sensitivity may be relevant to their ability to suppress colon carcinogenesis.

Acetylcysteine↗
PubMed1999

Regioselective synthesis and biological profiling of butyric and phenylalkylcarboxylic esters derivated from D-mannose and xylitol: influence of alkyl chain length on acute toxicity.

Regiospecific synthesis of 12 novel n-butyric and phenylalkylcarboxylic monoesters of mannose and xylitol was achieved. The strategy adopted, avoided a tedious intramolecular transesterification step, previously described for the synthesis of analogous compounds and permitted the facile synthesis of a new generation of stable derivatives. The general tolerance of the drugs has been assayed after intravenous administration of a bolus dose into mice. Monobutyric esters showed a low toxicity commensurate with the requirements for future development. A relationship was observed between chain length and toxicity. In contrast, phenylacetic, 3-phenylpropionic and 4-phenylbutyric esters were found to be toxic. Phenylbutyric esters induced marked and specific neuromuscular damage. Preliminary biological investigations of the new series of monobutyric esters showed them to retain the benificial biological properties of butyric acid whilst remaining relatively non toxic. They induced an inhibition of in vitro proliferation of 10 human cases of de novo acute myeloid leukemia (AML) primary cultures and AML established cell lines. AML blasts growth appeared to be blocked and cell differentiation was established. Transcription and expression of maturation markers and finally apoptosis were observed. Moreover, human gamma-chain hemoglobin (HbF) synthesis in erythroleukemia cells was stimulated by monobutyric esters. Mannose and xylitol butyric derivatives would appear to have exciting potential in treatment of beta-Hemoglobinopathies, sickle cell anemia and cancer.

Animals↗
PubMed2001

The effect of formulation and concentration of cholesteryl butyrate solid lipid nanospheres (SLN) on NIH-H460 cell proliferation.

Experimental factorial design was used to evaluate the influence of two factors involved in producing cholesteryl butyrate (chol-but) solid lipid nanospheres (SLN), microemulsion formulation and microemulsion/water ratio, on the effect of the SLN on the proliferation of NIH-H460, a non-small-cell lung carcinoma; six experimental settings were tested. The cells were treated with scalar concentrations of cholesteryl butyrate (from 0.008 to 1.000 mM) for each experimental condition; NIH-H460 cell growth was inhibited in all cases. The best experimental setting provided complete inhibition at 0.125 mM chol-but, while at the same concentration sodium butyrate provided only 38% inhibition.

Butyric Acid↗
PubMed1998

Vincristine- and cisplatin-induced apoptosis in human retinoblastoma. Potentiation by sodium butyrate.

Chemotherapy alone has largely been unsuccessful in controlling retinoblastoma growth, and has traditionally been limited in use as an alternative to irradiation for the treatment of retinoblastoma. Recently, clinical studies combining chemotherapy with local therapies, including radiotherapy, laser therapy or cryotherapy and in some cases, cyclosporine A, have been effective in treating retinoblastoma. Differentiating agents may also be combined with chemotherapy to enhance the action of cytotoxic drugs on tumor cell growth, although this approach has not been fully investigated in retinoblastoma. In this study, we evaluated the cytotoxic response of human retinoblastoma cell lines (Y79 and WERI-Rb1) to two chemotherapy agents commonly used in treating retinoblastoma, vincristine (VCR) and cisplatin (CDDP). Retinoblastoma cells have been shown to be sensitive to the differentiating agent sodium butyrate, and cell lines were also treated with a combination of VCR or CDDP with sodium butyrate, and the effects on retinoblastoma viability assessed. Both VCR and CDDP induced dose-dependent death of Y79 and WERI-Rb1 cells, accompanied by nuclear and cytoplasmic condensation and DNA laddering, features characteristic of apoptosis. Inhibitors of macromolecular synthesis, cycloheximide and actinomycin-D, significantly reduced VCR- and CDDP-induced apoptosis, although putative endonuclease inhibitors zinc sulphate and aurintricarboxylic acid had no apparent effect. Treatment with 0.5 mM or 1 mM sodium butyrate combined with VCR or CDDP significantly increased induction of apoptosis by these agents. This augmentation of chemotherapy-induced apoptosis may have implications for retinoblastoma therapy.

Antineoplastic Agents↗
PubMed2003

Up-regulation of the peroxisomal beta-oxidation system occurs in butyrate-grown Candida tropicalis following disruption of the gene encoding peroxisomal 3-ketoacyl-CoA thiolase.

In the yeast Candida tropicalis, two thiolase isozymes, peroxisomal acetoacetyl-CoA thiolase and peroxisomal 3-ketoacyl-CoA thiolase, participate in the peroxisomal fatty acid beta-oxidation system. Their individual contributions have been demonstrated in cells grown on butyrate, with C. tropicalis able to grow in the absence of either one. In the present study, a lack of peroxisomal 3-ketoacyl-CoA thiolase protein resulted in increased expression (up-regulation) of acetoacetyl-CoA thiolase and other peroxisomal proteins, whereas a lack of peroxisomal acetoacetyl-CoA thiolase produced no corresponding effect. Overexpression of the acetoacetyl-CoA thiolase gene did not suppress the up-regulation or the growth retardation on butyrate in cells without peroxisomal 3-ketoacyl-CoA thiolase, even though large amounts of the overexpressed acetoacetyl-CoA thiolase were detected in most of the peroxisomes of butyrate-grown cells. These results provide important evidence of the greater contribution of 3-ketoacyl-CoA thiolase to the peroxisomal beta-oxidation system than acetoacetyl-CoA thiolase in C. tropicalis and a novel insight into the regulation of the peroxisomal beta-oxidation system.

Acetyl-CoA C-Acetyltransferase↗