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PubMed1996

Treatment of left-sided ulcerative colitis with butyrate enemas: a controlled trial.

BACKGROUND: The colonic mucosa is highly dependent upon the presence of luminal nutrients. This dependence is most marked in the distal colon. The major luminal nutrients are short chain fatty acids that are produced as a by-product of colonic fermentation of carbohydrates. Butyrate appears to be the short chain fatty acid most avidly metabolized by the colonic mucosa. It has been suggested that ulcerative colitis is, at least in part, related to an energy deficiency state of the colonic mucosa which may be secondary to impaired short chain fatty acid production, uptake or utilization. The objective of this study was to determine if butyrate given as enema therapy is effective in the treatment of active distal ulcerative colitis. METHODS: Thirty-eight patients with distal ulcerative colitis were randomly assigned to receive nightly butyrate (n = 19) or saline/placebo (n = 19) enemas. Butyrate enemas consisted of 60 mL of 80 mM sodium butyrate titrated to a pH of 7.0. Patients were assessed clinically and endoscopically at baseline and at 3 and 6 weeks follow-up. Pre- and post-treatment mucosal biopsies were assessed histologically. Response to therapy was determined by changes in a 12-point clinical disease activity index score based on patient symptoms, endoscopic mucosal appearance and physicians' global assessment. RESULTS: Clinical improvement was noted in seven of 19 (37%) butyrate-treated patients and nine of 19 (47%) placebo-treated patients (P = 0.51). Clinical remission was achieved in three patients in each group (16%). No toxicity was observed in either treatment arm. CONCLUSIONS: The results suggests that once nightly 60 mL butyrate enemas (80 mmol/L) are not efficacious in the treatment of distal ulcerative colitis.

Adult↗
PubMed1997

n-butyrate downregulates the stimulatory function of peripheral blood-derived antigen-presenting cells: a potential mechanism for modulating T-cell responses by short-chain fatty acids.

Modulation of proliferative T-cell responses by n-butyrate has been suggested to result from direct interference with cell cycle progression. Considering the important role of antigen-presenting cells (APC) in T-cell activation, we were particularly interested in studying the impact of n-butyrate on these cells. We demonstrated that pretreatment of human peripheral blood mononuclear cells (PBMC) or monocytes with this agent resulted in a dose- and time-dependent downregulation of their capability to stimulate T-cell responses with a similar pattern of inhibition when this agent was present throughout the culture period. Pretreatment with n-butyrate was effective in preventing both alloresponses and T-cell proliferation to immobilized anti-CD3 monoclonal antibody (mAb) suggesting alteration of costimulatory function. Flow cytometric analysis revealed that interferon-gamma (IFN-gamma)-induced upregulation of B7-1 expression on monocytes was profoundly inhibited by n-butyrate. Furthermore, this agent significantly suppressed the expression of intercellular adhesion molecule-1 (ICAM-1) or lymphocyte function-associated antigen-3 (LFA-3). In contrast, constitutive as well as cytokine-induced expression of B7-2 was enhanced by n-butyrate. Additionally, in monocytes, but not in T cells, treatment with n-butyrate led to significant alteration of membrane integrity owing to apoptotic cell death. Our findings indicate that modulation of T-cell responses by n-butyrate could also result from altered APC function, possibly as a consequence of downregulating distinct adhesion and/or costimulatory receptors as well as of inducing apoptosis. A potential clinical relevance of short-chain fatty acids for reducing T-cell-mediated immune reactions via modulating APC function is speculated.

Antigen-Presenting Cells↗
PubMed1988

Sodium butyrate increases glucose transporter expression in LLC-PK1 cells.

The effect of sodium butyrate on the expression of the facilitated glucose transporter (GT) was investigated in the pig kidney cell line LLC-PK1. When cells were treated with butyrate, GT mRNA expression was remarkably enhanced with a maximal effect at 5 mM. Levels of GT mRNA were increased at 1 day after butyrate treatment and continued to increase for at least 4 days; however, acetate and propionate did not affect GT mRNA levels significantly. The induction of GT mRNA by butyrate was accompanied by an increase in GT function. The expression of GT mRNA decreased in HepG2, HT-29, and COS cells by treatment with butyrate for 1 day. Interestingly, glucose deprivation of LLC-PK1 cells reduced the induction of GT mRNA by butyrate, although starvation itself slightly enhanced steady-state GT mRNA levels. Therefore, expression of GT in LLC-PK1 cells is strongly induced by butyrate by a pathway that apparently depends on the presence of glucose in culture medium.

3-O-Methylglucose↗
PubMed1997

The effects of sodium butyrate on transcription are mediated through activation of a protein phosphatase.

In this study we have investigated the molecular mechanism by which sodium butyrate modulates gene expression when added to cultured cells. As a model system we used hepatoma tissue culture cells in which sodium butyrate treatment increases histone H1(0) mRNA level and decreases c-myc mRNA level. Because we observed that stimulation of histone H1(0) gene expression could take place in the absence of protein neosynthesis, we hypothesized that sodium butyrate induced a post-translational modification of a factor involved in the transcription process. Using different types of well known kinase and phosphatase inhibitors, we studied the implication of kinase or phosphatase activity in this pathway. Interestingly, cell treatment with potent serine-threonine-phosphatase inhibitors, calyculin A or okadaic acid, prevented the regulation of both histone H1(0) and c-myc gene expressions by sodium butyrate. On the other hand, the tyrosine phosphatase inhibitor, vanadate, or the protein kinase C inhibitor, staurosporine, did not significantly modify sodium butyrate effects. Using protein phosphatase 1 and 2A for in vitro assays, we found a 45% increase of phosphatase activity after cell treatment by sodium butyrate, possibly due to a protein phosphatase 1-type protein phosphatase. These data strongly suggest that signaling pathway(s) triggered by sodium butyrate to modulate gene expression involve(s) a serine-threonine-phosphatase activity.

Butyrates↗
PubMed1991

Influence of butyrate on lipid metabolism, survival, and differentiation of colon cancer cells.

The present work was designed to study the differentiating effect of butyrate on LS174T cells after modification of their lipids with long-chain fatty acid (LCFA) supplementation. The LCFAs 18:1(n-9), 18:2(n-6), 20:4(n-6), 20:5(n-3), and 22:6(n-3) bound to added to the media of confluent cells for eight days. The fatty acid-to-albumin ratio was 3:1. The concentration of fatty acids in the media was 100 microM. On the last day, half of the flasks were treated with 2 mM butyrate. The data indicate that supplementation with polyunsaturated LCFAs having 20-22 carbon atoms resulted in a significant reduction in cell density and viability, whereas all LCFA supplementation reduced differentiation as measured by alkaline phosphatase activity. Butyrate treatment increased the density, viability, and differentiation of the tumor cells. The effect of butyrate on differentiation was mainly with cells supplemented with 18:1, 20:5, and 22:6. In the absence of LCFA supplementation, butyrate reduced the concentration of 22:5(n-6) in the cellular lipids. Also, butyrate modified the LCFAs incorporated in cells supplemented with 18:2 and 20:5, with changes occurring in 20:5(n-3), 22:5(n-3), and 22:5(n-6). Thus the present study suggests an interaction between butyrate and LCFA on differentiation and LCFA metabolism of human colon cancer cells.

Adenocarcinoma↗
PubMed1993

Differential effect of butyrate on lipids of human colon cancer cells.

Recently, we demonstrated that treatment of LS174T cells with 2 mM butyrate for one day had a significant effect on the composition of cellular fatty acids. In an attempt to further explore this phenomenon, we investigated the effect of long-term butyrate treatment in the presence of different fatty acids in the medium on cellular phospholipids (PLs) and triacylglycerol (TG). Cells were supplemented with 100 microM sodium salts of 18:2 (n-6), 20:4 (n-6), 20:5 (n-3), or 22:6 (n-3) as a fatty acid-free-albumin complex. The molar ratio of the albumin and these long-chain fatty acids (LCFAs) was 3:1. One-half of these cultures were supplied with 2 mM butyrate, and the pH was adjusted to 7.4. The supplementation of the LCFAs and butyrate was maintained for eight days. The present study indicates that butyrate had a differential effect on the fatty acid composition of PLs and TG of LS174T cells. This includes an increase in monounsaturates and elongation of the supplemented LCFA, and this effect was more pronounced on TG than PL fatty acids. Butyrate resulted in a significant reduction in polyunsaturated fatty acid concentration only in PLs. In general, butyrate decreased the unsaturation index (UI) of the PLs but increased that of TG. The present study also confirmed our previous observation regarding the effect of LCFAs on cellular lipids. PL and TG fatty acid chain lengths reflect those of supplemented fatty acids. The UI of these two lipid fractions increased more with supplementation of n-3 than n-6 fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Butyrates↗
PubMed1984

Sodium butyrate induces histone hyperacetylation and differentiation of murine embryonal carcinoma cells.

Cells from embryonal carcinoma (EC) lines 6050AJ and PCC4.aza 1R differentiate in response to treatment with sodium butyrate as well as retinoic acid (RA) or hexamethylenebisacetamide (HMBA). Murine 6050AJ EC cells exposed to sodium butyrate possess hyperacetylated forms of histones H4 and altered forms of histones H2a and H2b, whereas histones from cells treated with other inducers appear to be unaffected. These results might indicate that the mechanism by which sodium butyrate promotes differentiation of EC cells is different from the ways in which RA and HMBA act. Differentiation-defective PCC4(RA)-1 EC cells fail to respond to RA, presumably because they possess minimal amounts of active binding protein for RA (cRABP). Sodium butyrate treatment of these cells results in only a modest level of differentiation. On the other hand, exposure to sodium butyrate plus RA leads to extensive differentiation. As is the case with 6050AJ cells, PCC4(RA)-1 cells treated with sodium butyrate also contain hyperacetylated histones. Furthermore, these cells now possess high levels of cRABP. The latter observations suggest that sodium butyrate has the ability to reactivate a silent cRABP gene in PCC4(RA)-1 cells and thereby lead to extensive differentiation via the retinoid pathway when RA is added.

Acetylation↗
PubMed1990

Unusual c-fos induction upon chromaffin PC12 differentiation by sodium butyrate: loss of fos autoregulatory function.

Induction of PC12 pheochromocytoma cells neuronal differentiation upon treatment with nerve growth factor (NGF) is accompanied by a coupled stimulation of c-fos and c-jun oncogene transcription. We found that induction of c-fos and c-jun proto-oncogene mRNAs levels following the endocrine differentiation of PC12 cells by sodium butyrate is uncoupled. While c-fos mRNA level increased within minutes, the content of c-jun mRNA was significantly elevated only 24 hours after treatment. Continuous presence of sodium butyrate for 72 hours resulted in stable high levels of c-fos and c-jun mRNAs. Gene transcription of the other members of the jun family, jun B and jun D, was not significantly modified at any induction time. The early accumulation of c-fos mRNA was accompanied by increased levels of c-Fos protein. While the NGF-induced c-Fos protein migrates with an apparent homogeneous molecular weight of 62 kDa, the sodium butyrate-stimulated Fos protein is of heterogeneous lower molecular weight. The different gel mobility of the Fos immunoreactive bands induced by sodium butyrate and the sustained Fos mRNA levels after induction suggested that the sodium butyrate-induced c-Fos protein could be non-functional in the autoregulation of the c-fos gene. Gel shift analysis showed unimpaired capacity of the butyrate-induced c-Fos protein to participate in the formation of transcriptional complexes with the Jun/AP-1 protein. However, transfection experiments indicate that the sodium butyrate-induced c-Fos protein is not able to negatively trans-regulate the c-fos promoter.

Adrenal Gland Neoplasms↗
PubMed1992

Two cytotoxic cell proteinase genes are differentially sensitive to sodium butyrate.

The 5'-flanking regions of two cytotoxic cell protease genes, CCP1 and 2, are sufficient to confer cytotoxic T lymphocyte-specific expression when fused to a reporter gene. The two regulatory regions are, however, differentially sensitive to treatment of the recipient cell, MTL 2.8.2, with sodium butyrate. With CCP1 a six-fold increase in cat expression was observed, whereas CCP2 was insensitive to the butyrate treatment. One major butyrate-sensitive regions was defined in the CCP1 5'-flanking sequence between -243 to -112 and another less effective one between-682 to -427. These fragments of DNA were also able to confer responsiveness to butyrate when ligated to a heterologous fos promoter. These sequences within the 5' flank of CCP1 share homology with other elements that have been defined as butyrate-responsive. We believe that our results argue against a pleiotropic affect of butyrate such as histone acetylation. More likely sodium butyrate is mediating a specific stimulation of transcription through modification of the activities of selected transcriptional regulatory proteins that in turn affect their interactions with proteins bound to the promoter.

Animals↗
PubMed1998

Effects of 5-azacytidine and butyrate on differentiation and apoptosis of hepatic cancer cell lines.

OBJECTIVE: To determine the cellular effects of 5-azacytidine (5-azaC) and sodium butyrate on two human liver cancers, HepG2 and Hep3B. SUMMARY BACKGROUND DATA: Primary liver cancer is a significant health problem; treatment options are limited and prognosis is poor. Recent studies have focused on the role that programmed cell death (i.e., apoptosis) plays in both normal and neoplastic growth: certain genes can either suppress (e.g., Bcl-2, Bcl-xL) or promote (e.g., Bik, Bax, Bak) apoptosis. The identification of novel agents targeted to specific molecular pathways may be beneficial in the treatment of this disease. METHODS: Human liver cancer cell lines HepG2 and Hep3B were treated with 5-azaC alone, butyrate alone, or 5-azaC and butyrate. Morphologic and proliferative changes were assessed by light microscopy and 5-bromo-2'-deoxyuridine staining; flow cytometry was used to determine cell cycle characteristics. Apoptosis was assessed by DNA laddering and the in situ apoptosis detection assay using the TdT-mediated dUTP nick end labeling method. In addition, total RNA and protein were analyzed by ribonuclease protection and Western blot, respectively, to assess changes in the expression of apoptosis-related genes. RESULTS: Treatment with either 5-azaC or butyrate inhibited cell growth and induced apoptosis in both HepG2 and Hep3B cells; the combination of 5-azaC and butyrate was not more effective than either agent alone. 5-azaC alone resulted in a more differentiated-appearing morphology and G2 cell cycle arrest in both cell lines. Treatment with 5-azaC or butyrate affected the expression levels of proteins of the Bcl-2 family. CONCLUSIONS: Both 5-azaC and butyrate induced apoptosis in the HepG2 and Hep3B liver cancer cells; 5-azaC treatment alone produced G2 arrest in both cell lines. Proteins of the Bcl-2 family may play a role in the cellular changes that occur with treatment, but further studies are required to define this potential role. Products of the apoptotic pathway may prove to be useful therapeutic targets in the treatment of hepatic cancers.

Antimetabolites, Antineoplastic↗
PubMed1993

Effect of sodium butyrate on glucose transport and glucose-phosphorylating enzymes in RIN-m5F cells.

Sodium butyrate is widely used to differentiate insulinoma cell lines. However, sodium has been shown to decrease glucose phosphorylation in the liver and heart and decrease the expression of glucose transporter. Since these mechanisms are essential for glucose-induced insulin secretion, the ultimate function of the pancreatic beta-cell, we investigated the effect of sodium butyrate on both glucose-phosphorylating enzymes as well as glucose transport in the pancreatic cell line RIN-m5F. Treatment of RIN-m5F cells with 2.5 mM sodium butyrate for 72 h increased by twofold both hexokinase and glucokinase (GK) activities, as well as the gene expression of GK. Sodium butyrate treatment had no effect on GLUT-1 mRNA levels but increased the GLUT-2 mRNA 3.7-fold. Kinetic analysis of 2-deoxyglucose transport displayed a single curve with Km = 1.2 mM and Vmax = 10.9 pmol/micrograms protein/min in the untreated cells, values similar to the low Km glucose transport reported in the pancreatic beta-cells. This low Km transport component markedly decreased with sodium butyrate treatment, and interestingly a second component with a higher Km appeared, consistent with the increase in GLUT-2 mRNA. We conclude that the differentiating action of sodium butyrate involves increases in GK and GLUT-2 gene expression, which characterizes the differentiated state of the pancreatic beta-cell. However, the inhibitory effect of sodium butyrate on low Km glucose transport needs to be considered in the use of this compound to promote differentiation.

Animals↗
PubMed1995

Butyrate in the treatment of sickle cell disease and beta-thalassemia.

The search for, and discovery of, a physiologic model in which the developmentally regulated switch from fetal to adult globin gene expression could be prevented has resulted in the development of a new class of therapeutic agents, consisting of simple fatty acids, such as butyric acid, for the treatment of the beta-hemoglobinopathies. Butyrate and related drugs stimulate fetal (gamma-) globin gene expression in erythroid cells cultured from patients, and in chicken, ovine, and primate animal models. The butyrates are perhaps the first class of drugs designed to transcriptionally activate specific genes--in this particular case, to reactivate the developmentally silenced fetal globin genes. Phase I-II clinical trials resulting from this basic research have been initiated on a small scale during the past 3 years. Analysis of two butyrate-derived therapeutic agents, one delivered intravenously and one orally, has shown initial efficacy in stimulating fetal hemoglobin expression in 50% to 85% of patients. Correction of the anemia from the beta-hemoglobinopathy has followed induction of fetal globin, and has been adequate to eliminate the need for erythrocyte transfusions in some patients with beta-thalassemia. These compounds have been relatively safe and without generalized cytotoxicity in patients, but drug tolerance develops in some patients after prolonged therapy. Third-generation, small two- to five-carbon butyrate derivatives are in development. The molecular basis for butyrate action is being defined. Binding of putative regulatory proteins to a specific region of the gamma-globin promoter is altered in vivo in patients receiving butyrate therapy. Further analysis of the mode of action may contribute to development of other therapeutic agents designed to regulate gene transcription.

Anemia, Sickle Cell↗
PubMed1981

Selective inhibition by sodium butyrate of glucocorticoid-induced tyrosine aminotransferase synthesis in hepatoma tissue-cultured cells.

Sodium butyrate in a 5 mM concentration prevents the induction of tyrosine aminotransferase in hepatoma culture cells, without affecting the basal level of the enzyme. This effect is reversible immediately after the removal of butyrate, or after a lag, if butyrate was present for more than 2 h. Neither the amount of cellular RNA nor the rate of total RNA synthesis were affected by sodium butyrate. Furthermore, butyrate does not inhibit protein synthesis: [35S]methionine incorporation into proteins, measured in a reticulocyte lysate system, shows no significant difference between the translation capacity of the RNAs from butyrate-treated cells and from dexamethasone-induced or uninduced cells. Nevertheless, when tyrosine aminotransferase was isolated from the translation products by its specific antiserum and analyzed by gel electrophoresis, we observed that the amount of the enzyme synthetized in the presence of RNAs from dexamethasone/butyrate-treated cells was strongly diminished relative to that synthesized in the presence of RNA from dexamethasone-induced cells. These experiments indicate that the treatment of the cells with butyrate decreases the activity of the specific messenger RNA for tyrosine aminotransferase to a level close to the basal level.

Animals↗
PubMedDate not supplied

Contrasting effects of butyrate on the expression of phenotypic markers of differentiation in neoplastic and non-neoplastic colonic epithelial cells in vitro.

The in vitro effect of butyrate on expression of differentiation markers in colonic epithelial cells was assessed in the colon cancer cell line, LIM1215 and in epithelial cells isolated from a surgically resected histologically normal colon. Markers used to assess cell differentiation were: net glycoprotein synthesis ([3H]-glucosamine uptake) expressed relative to net protein synthesis ([14C]-leucine uptake), and the expression of the brush border glycoproteins (alkaline phosphatase and carcino-embryonic antigen) in cell homogenates calculated relative to cellular protein content. In response to 24 h exposure to 1 mmol/L butyrate, all markers significantly increased in LIM1215 cells whereas they all significantly decreased in isolated colonic epithelial cells under identical culture conditions. Similar effects were seen at butyrate concentrations of up to 4 mmol/L. Butyrate suppressed proliferation of LIM1215 cells but had no consistent effect on [3H]-thymidine uptake by, or DNA content of, normal epithelial cells. Additional experiments found no evidence of a toxic effect of butyrate at those concentrations nor of an alteration of cell responsiveness to butyrate due to the isolation process itself. In contrast to its differentiative effect on neoplastic cells, butyrate reduces the expression of phenotypic markers of differentiation in vitro in colonic epithelial cells from non-neoplastic mucosa.

Butyrates↗
PubMed1998

The characterization of butyrate transport across pig and human colonic luminal membrane.

1. Luminal membrane vesicles (LMV) were isolated from human and pig colonic tissues. They were characterized in terms of purity and ability to transport [14C]butyrate. 2. The activity of cysteine-sensitive alkaline phosphatase, and the abundance of villin, NHE2 and NHE3 proteins, markers of the colonic luminal membrane, were significantly enriched in the LMV compared with the original cellular homogenate. The LMV were free from contamination by other cellular organelles and basolateral membranes, as revealed by the negligible presence of either specific marker enzyme activity or characteristic immunogenic protein. 3. The transport of butyrate into the luminal membrane vesicles was enhanced 5-fold at pH 5.5 compared with pH 8.0. Butyrate transport was temperature dependent, and was stimulated in the presence of an outward-directed anion gradient in the order of butyrate > bicarbonate > propionate > chloride. Kinetic analysis of increasing substrate concentration showed saturation kinetics with an apparent Km value of 14.8 +/- 3.6 mM and a Vmax of 54 +/- 14 nmol min-1 (mg protein)-1. 4. Butyrate transport was significantly reduced in the presence of short chain fatty acids (SCFA), acetate, propionate and other monocarboxylates (pyruvate and L-lactate). Butyrate uptake was inhibited by several cysteine group modifying reagents such as p-chloromercuribenzosulphonic acid (pCMBS), p-chloromercuribenzoate (pCMB), mersalyl acid and HgCl2, but not by the stilbene anion exchange inhibitors, 4,4'-diisothiocyanostilbene-2,2'-disulphonate (DIDS) and 4,4'-dinitrostilbene-2,2'-disulphonate (SITS). 5. The described properties of butyrate transport across the luminal pole of the colon suggest the involvement of a carrier protein, in the form of a pH-activated anion exchange process. The transporter is distinct from the erythrocyte band-3 type anion exchanger and may belong to the monocarboxylate-type transport proteins (MCT1).

Animals↗
PubMed1984

Sodium butyrate-induced adhesion in mastocytoma cells.

Sodium butyrate induced adhesion of cultured mastocytoma p-815 cells to the surface of a standard tissue culture grade petri dish. The ratio of the number of adherent cells to that of total cells (adherent plus floating cells) was dependent on the serum concentration and on the dose of sodium butyrate. During approximately the first 6 hr after the addition of sodium butyrate, no cells adhered. The optimum conditions for adhesion were provided by 2 mM sodium butyrate and 15% fetal calf serum, 44 hr after addition of this compound. Morphologically, adherent cells consisted of spindle-shaped and round cells: the latter clustered to the former. Low concentrations of actinomycin D (0.005 microgram/mL) and of cycloheximide (0.5 microgram/mL) inhibited cell adhesion. Adherent cells were easily detached by 0.25% trypsin-0.02% EDTA but not by EDTA alone. Adherent mastocytoma cells which were cultured in the presence of 2 mM sodium butyrate, re-adhered to the surface of the dish. The ratio of adhesion in the second dish, however, was very low (35% after 2 hr incubation). Radioactive iodinated surface proteins of butyrate-treated adherent cells showed two new bands (70,000 and 92,000 D) which were not detected in control cells, but there was no difference in the extent of labeling of high molecular weight protein (250,000 D) between butyrate-treated and control cells.

Animals↗
PubMed1985

Effects of sodium n-butyrate on entry into S phase in resting rat 3Y1 cells infected with simian virus 40.

In quiescent rat 3Y1 fibroblasts infected with simian virus 40 (SV40), sodium butyrate elongated the time lag before entry into S phase in a concentration-dependent fashion. In spite of the elongated time lags, SV40-infected cells entered S phase in a very synchronous mode, irrespective of the butyrate concentrations. The elongated time lag seemed to be at least partially due to a delayed synthesis and a delayed accumulation of large T antigen caused by butyrate. The entry into S phase was also delayed even when butyrate was added to the cultures after expression of T antigen to an extent sufficient for untreated cells to enter S phase. This suggests that butyrate may also inhibit a cellular event(s) that is required for entry into S phase after expression of the T antigen. In contrast, serum-stimulated cells were more sensitive to butyrate with respect to entry into S phase than SV40-infected cells, and the distribution of the time lag among cell populations increased (i.e., asynchrony in entry into S phase increased) with an increase in the butyrate concentration.

Animals↗
PubMed1994

n-Butyrate, a cell cycle blocker, inhibits the replication of polyomaviruses and papillomaviruses but not that of adenoviruses and herpesviruses.

Small DNA viruses are dependent on the interaction of early proteins (such as large T antigen) with host p53 and Rb to bring about the G1-to-S cell cycle transition. The large DNA viruses are less dependent on host regulatory genes since additional early viral proteins (such as viral DNA polymerase, DNA metabolic enzymes, and other replication proteins) are involved in DNA synthesis. A highly conserved domain of large T antigen (similar to the p53-binding region) exclusively identifies papovavirus, parvovirus, and papillomaviruses from all other larger DNA viruses and implies a conserved interaction with host regulatory genes. In this report, we show that 3 to 6 mM butyrate, a general cell cycle blocker implicated in inhibition of the G1-to-S transition, inhibits DNA replication of polyomavirus and human papillomavirus type 11 but not the replication of larger DNA viruses such as adenovirus types 2 and 5, herpes simplex virus type 1, Epstein-Barr virus, and cytomegalovirus, which all bypass the butyrate-mediated cell cycle block. This butyrate effect on polyomavirus replication is not cell type specific, nor does it depend on the p53 or Rb gene, as inhibition was seen in fibroblasts with intact or homozygous deleted p53 or Rb, 3T6 cells, keratinocytes, C2C12 myoblasts, and 3T3-L1 adipocytes. In addition, butyrate did not inhibit expression of polyomavirus T antigen. The antiviral effect of butyrate involves a form of imprinted state, since pretreatment of cells with 3 mM butyrate inhibits human papillomavirus type 11 DNA replication for at least 96 h after its removal. Butyrate, therefore, serves as a molecular tool in dissecting the life cycle of smaller DNA viruses from that of the larger DNA viruses in relation to the cell cycle.

Adenoviridae↗