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At least 595 records · Page 33Linked to original sources
PubMed2000

The congenital chloride diarrhea gene is expressed in seminal vesicle, sweat gland, inflammatory colon epithelium, and in some dysplastic colon cells.

Congenital chloride diarrhea (CLD) is an autosomal recessive disorder of intestinal electrolyte transportation caused by mutations in the anion transporter protein encoded by the down-regulated in adenoma (DRA), or CLD, gene. In this study, in situ hybridization and immunohistochemistry were performed to investigate the expression of CLD in extraintestinal normal epithelia and in intestinal inflammatory and neoplastic epithelia. The expression of the closely related anion transporter diastrophic dysplasia sulfate transporter, DTDST, was also examined and compared with that of CLD in colon. The only extraintestinal tissues showing CLD expression were eccrine sweat glands and seminal vesicles. In inflammatory bowel disease and ischemic colitis, expression of CLD mRNA in colon epithelium was similar to histologically normal colon epithelium, but the protein was found deeper in crypts, including proliferative epithelial cells. In intestinal tumors, the expression pattern of CLD was dependent on the differentiation status of the tissue studied: epithelial polyps with no or minor dysplasia showed abundant expression, whereas adenocarcinomas were negative. The DTDST gene was abundantly expressed in the upper crypt epithelium of colonic mucosa.

Chlorides↗
PubMed2000

Lack of Pseudomelanosis coli in colonic adenomas suggests different pathways of apoptotic bodies in normal and neoplastic colonic mucosa.

Pseudomelanosis coli is characterized by pigment deposition in the lamina propria and caused by increased epithelial apoptosis. Pseudomelanosis coli is absent in colonic neoplasia. The aim of our studies was to investigate this phenomenon in more detail. Apoptotic fragments of epithelial cells and their distribution, cell proliferation (Ki-67, MIB 1 immunostaining), macrophages (CD68 immunostaining), Bcl-2 expression and apoptosis [terminal-deoxynucleotidyl-transferase mediated dUTP fluorescein nick end labeling (TUNEL) assay] were studied in adenomas arising in normal and melanotic colonic mucosa, in normal colonic mucosa and colonic mucosa with pseudomelanosis alone. In adenomas, we found 7.0 apoptotic bodies per 100 epithelial cells in the epithelial layer and only 0.2 apoptotic bodies per high power field (HPF) in the lamina propria. In contrast, in melanotic mucosa 1.7 apoptotic bodies per 100 epithelial cells in the epithelial layer and 2.5 per HPF in the lamina propria were found. Our results show that apoptotic fragments remain in the neoplastic (adenomatous) epithelium and do not reach (at least in higher amounts) the lamina propria. They can, therefore, not contribute to the development of pseudomelanosis in these lesions. However, macrophages are diminished in adenomas. Proliferation (Ki-67) and also Bcl-2 expression are highly increased in adenomas. The pathway of mucosal macrophages is also discussed.

Adenoma↗
PubMed1986

Beta-adrenergic control of motility in the rat colon. I. Evidence for functional separation of the beta 1- and beta 2-adrenoceptor-mediated inhibition of colon activity.

The beta-adrenoceptor-mediated inhibitory response in isolated rat colon strips of beta-adrenoceptor agonists (isoproterenol, terbutaline, prenalterol) in the absence and presence of the selective beta-adrenoceptor antagonists metoprolol (beta 1) and IPS 339 (beta 2) demonstrates that both beta 1- and beta 2-adrenoceptors are involved in the inhibition of colonic motility. Neuronal blockade induced by tetrodotoxin suppressed the relatively high (68%) maximal response of prenalterol (partial beta-adrenoceptor agonist) to 23%. The concentration-response curves for terbutaline (beta 2-selective agonist) and isoproterenol (nonselective agonist) were not influenced by tetrodotoxin. The results thus indicate that the beta-adrenergic inhibition of spontaneous activity in the rat colon strip may be mediated at two functional levels within the colon wall: either by beta 2-adrenoceptors in the smooth muscle layer or by beta 1-adrenoceptors in the intramural ganglionic plexuses, which by neuronal elements are coupled to the effector smooth muscle.

Adrenergic beta-Agonists↗
PubMed1993

Preservation of the ileocecal valve and right colon in total colonic aganglionosis.

A new surgical technique for the treatment of total colonic aganglionosis is described. Preservation of the right colon and the ileocecal valve is possible by performing an end-to-back anastomosis between a prececal short ileum segment and the uneffected ileum, and by creating a side-to-side anastomosis between an isolated ileal loop and the right colon. The ileorectal anastomosis is performed with a curved EEA 21 circular stapler (USSC, Norwalk, CT). After a neonatal ileostomy, the operation is performed as a one-stage procedure. The advantage of preserving the right colon and the ileocecal valve is discussed.

Anastomosis, Surgical↗
PubMed2000

Evidence for the presence of cGMP-dependent protein kinase-II in human distal colon and in T84, the colonic cell line.

Heat-stable enterotoxin (STa) stimulates intestinal Cl(-) secretion by activating guanylate cyclase C (GCC) to increase intracellular cyclic GMP (cGMP). In the colon, cGMP action could involve protein kinase (PK) G-II or PKA pathways, depending on the segment and species. In the human colon, both PKG and PKA pathways have been implicated, and, therefore, the present study examined the mechanism of cGMP-mediated Cl(-) transport in primary cultures of human distal colonocytes and in T84, the colonic cell line. Both cell preparations express mRNA for CFTR, Na(+)-K(+)-2Cl(-) cotransporter (NKCC1), GCC and PKG-II as detected by RT-PCR. The effects of STa and the PKG-specific cGMP analogues, 8Br-cGMP and 8pCPT-cGMP, on Cl(-) transport were measured using a halide-sensitive probe. In primary human colonocytes and T84 cells, STa, the cGMP analogues and the cAMP-dependent secretagogue, prostaglandin E(1) (PGE(1)), enhanced Cl(-) transport. The effects of 8Br-cGMP and 8pCPT-cGMP suggested the involvement of PKG, and this was explored further in T84 cells. The effects of 8pCPT-cGMP were dose-dependent and sensitive to the PKG inhibitor, H8 (70 microM), but H8 had no effect on PGE(1)-induced Cl(-) secretion. In contrast, a PKA inhibitor, H7 (50 microM), blocked PGE(1)-mediated but not 8pCPT-cGMP-induced Cl(-) transport. 8pCPT-cGMP enhanced phosphorylation of the PKG-specific substrate, 2A3, by T84 membranes in vitro. This phosphorylation was inhibited by H8. These results strongly suggest that cGMP activates Cl(-) transport through a PKG-II pathway in primary cells and in the T84 cell line of the human colon.

Biological Transport↗
PubMed2000

Intraoperative assessment of colonic perfusion using scanning laser Doppler flowmetry during colonic resection.

BACKGROUND: Ischemia occurring on mobilization and mesenteric division is thought to be a major factor in the etiology of anastomotic dehiscence after colorectal resection. This study assessed the ability of the new technique of scanning laser Doppler flowmetry to measure changes in human colonic perfusion during mobilization at and adjacent to the anastomotic site. STUDY DESIGN: Colonic perfusion was measured in 10 patients undergoing large-bowel resection by making laser Doppler scans of the proximal bowel before mobilization, after mobilization and mesenteric division, and after resection of the specimen. Mean perfusion was calculated within 1-cm2 regions of interest, each of which contained 1,750 individual measurements of perfusion. These regions represented the anastomosis site and adjacent areas 1 cm and 2 cm proximal and distal to this. The results were expressed as mean perfusion units (PUs). RESULTS: After mobilization, there were significant decreases in perfusion in all the subjects between each time point and in all areas of the colon scanned. Median perfusion at the anastomosis site was 491 PUs before mobilization, and this fell to 212 PUs after mobilization, representing a decrease of 57%; the median within-person decrease was also 57% (p < 0.01). There was a gradient of reduced perfusion between the area 2 cm proximal to the mesenteric division (median within-person fall 25%; p < 0.05) and the area 2 cm distal to the mesenteric division (median within-person fall 84%; p < 0.01). After resection of the specimen, perfusion increased slightly at the anastomosis site to a median of 240 PUs (median within-person fall 41%; p < 0.01), but 2 cm proximal to this, median perfusion remained depressed at 330 PUs. CONCLUSIONS: This new technique can be used intraoperatively and appears to overcome the limitations of single-point laser Doppler flowmetry. In this small preliminary study, it measured large decreases in colonic perfusion during mobilization, and it may have widespread clinical applications.

Aged↗
PubMed1984

A colon-specific drug-delivery system based on drug glycosides and the glycosidases of colonic bacteria.

Steroid glycosides and the unique glycosidase activity of the colonic microflora form the basis of a new colon-specific drug-delivery system. Drug glycosides are hydrophilic and, thus, poorly absorbed from the small intestine. Once such a glycoside reaches the colon it can be cleaved by bacterial glycosidases, releasing the free drug to be absorbed by the colonic mucosa. This concept was illustrated with dexamethasone 21-beta-D-glucoside (1) and prednisolone 21-beta-D-glucoside (2), two prodrugs that may be useful in treating inflammatory bowel disease. Hydrolysis of the prodrugs by beta-glucosidase and fecal homogenates in vitro released the free steroids. Glucosides 1 and 2 were administered to rats intragastrically to determine when and where the free steroids were released. Unmodified dexamethasone (3) and prednisolone (4) were also given to rats intragastrically to compare absorption of the glucosides with the free steroids. Both glucosides were found to reach the rat lower intestine in 4-5 h, where they were rapidly hydrolyzed, releasing the free steroids. Delivery of steroid 3 (via glucoside 1) was more specific than that of steroid 4 (via glucoside 2): nearly 60% of an oral dose of glucoside 1 reached the cecum, whereas less than 15% of glucoside 2 reached the cecum. When free steroids 3 and 4 were administered orally, they were almost exclusively absorbed in the small intestine: less than 1% of an oral dose of each reached the cecum.

Administration, Oral↗
PubMed1988

New actinomycin D analogues as superior chemotherapeutic agents against primary and advanced colon tumors and colon xenografts in nude mice.

"Reverse" analogues (RAD's) of actinomycin D (AMD) and their antitumor activity against mouse and human colon tumor cells are reported. RAD's are tetracyclic, and they have an oxazole ring fused on the tricyclic phenoxazine chromophore of AMD. The oxazole ring in RAD is substituted at the C-2 carbon with either a CH3 (in RAD I), a C6H5 (in RAD II), or a CH2CONH(CH2)4NH2 (in RAD III) group. In tumor cells and rat hepatic microsomes, RAD's are metabolized to a tricyclic "symmetrical" analogue of AMD (SAD) with the loss of the oxazole ring and its substituents. RAD and SAD are very active in priming superoxides in the presence of microsomal enzymes as well as in inhibiting the synthesis of DNA and the growth of human colon tumor HT-29 cells in vitro. RAD III and SAD efficiently cleave closed circular plasmid pBR322 DNA like the antitumor agent bleomycin. In addition to their strong inhibitory activity against P388 and B16 tumors in vitro and in vivo, RAD III and SAD demonstrate high levels of activity against primary C26 and advanced C38 colon tumors in mice and against a xenograft of human colon adenocarcinoma CX-1 in athymic mice. In all these biological activities, the analogues demonstrate superiority to AMD in several experimental tumors. Also, the analogues, in contrast to AMD, show reduced toxicity in tumor-free mice, which is possibly due to the metabolic deactivation of SAD in host organs.

Animals↗
PubMed2000

Evidence for a Na+-H+ exchange across human colonic basolateral plasma membranes purified from organ donor colons.

The mechanism(s) of electrolyte transport across the human colonic contraluminal domain is not well understood. Current studies were undertaken to develop a technique for the isolation and purification of the human colonic basolateral membrane vesicles (BLMV) and to examine the presence of a Na+-H+ exchange process in these membranes. BLMV were purified from mucosal scrapings of organ donor proximal colons utilizing a Percoll density gradient centrifugation technique, and Na+ transport was examined utilizing a rapid filtration, technique. Our data demonstrate that purified basolateral membranes were enriched 10- to 11-fold in Na+, K+-ATPase activity compared to crude homogenate. Results consistent with the Na+-H+ exchange in BLMV are as follows: (1) an outwardly directed H+ gradient stimulated 22Na uptake; (2) 22Na uptake was markedly inhibited by EIPA and amiloride; (3) H+-gradient-stimulated 22Na uptake was not inhibited by bumetanide, SITS, DIDS, acetazolamide, phenamil and benzamil; (4) 22Na uptake was voltage insensitive; (5) 22Na uptake demonstrated saturation kinetics; (6) 22 Na uptake was markedly inhibited by Na+ and Li+ but was unaffected by N-methyl glucamine+, choline+, and NH4+. Immunoblotting studies demonstrated this Na+-H+ exchanger isoform to be represented by NHE1. In conclusion, a technique has been established for the purification of functional human proximal colonic BLMV, and an electroneutral Na+-H+ exchange process has been demonstrated in these membranes.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2000

The addition of low-dose leucovorin to the combination of 5-fluorouracil- levamisole does not improve survival in the adjuvant treatment of Dukes' C colon cancer. IKN Colon Trial Group.

PURPOSE: To assess the effect of the addition of leucovorin to the combination of 5-fluorouracil (5-FU)-levamisole on recurrence risk and overall survival in patients after a resection with curative intent of a Dukes' C colon cancer. PATIENTS AND METHODS: Five hundred patients with Dukes' C colon cancer were randomly assigned to adjuvant treatment for one year with 5-fluorouracil (450 mg/m2 i.v. weekly) and levamisole (150 mg p.o. every two weeks), the C-group or with leucovorin (20 mg/m2 i.v.), 5-fluorouracil and levamisole, the L-group. The median follow-up for patients still alive is 36 months. Four patients were ineligible because of advanced disease at the time of randomisation. RESULTS: Sixty percent of the patients have completed all courses of chemotherapy. Of the remaining 40% of the patients who did not complete one-year treatment with chemotherapy, 46% discontinued because of toxic and/or emotional reasons. They were equally divided over both treatment arms. The addition of leucovorin increased toxicity (especially mucositis and conjunctivitis) without a significant increase in treatment withdrawal. Five-year disease-free interval (C-group: 49%, L-group: 46%; log-rank test, P = 0.86) and overall survival (C-group: 55%, L-group: 59%, log-rank test: P = 0.96) were very similar in both treatment arms. CONCLUSIONS: The addition of low dose leucovorin to the combination of 5-fluorouracil and levamisole in a 12-month adjuvant therapy for curatively resected Dukes' C colon cancer patients does not improve disease-free interval nor overall survival. The addition of leucovorin to the combination of 5-FU levamisole increases toxicity. Therefore leucovorin 5-FU levamisole is not recommended in a 12 months adjuvant regime of Dukes' C colon cancer.

Adenocarcinoma↗
PubMed2001

Effect of bile salts on colonic mucus secretion in isolated vascularly perfused rat colon.

Mainly composed of mucins, mucus secreted by goblet cells in the intestinal epithelium is critically involved in the protection of the gastrointestinal mucosa. The hypothesis that bile and some bile salts can induce mucus secretion was tested in the isolated perfused rat colon. Mucus release was evaluated using enzyme-linked immunosorbent assays and supported by histological analysis. Luminal administration of bile extract (1%) provoked mucus secretion in the rat colon. Deoxycholate (0.5-10 mM) induced a dose-dependent increase in rat colonic mucus release. Chenodeoxycholate (10 mM) and hyodeoxycholate (10 mM) also evoked mucus discharge, whereas 10 mM cholate, 10 mM ursodeoxycholate, or Tween-20 did not release mucus. Taurine-conjugated bile salts (deoxycholate, hyodeoxycholate, and chenodeoxycholate) were less potent mucus secretagogues than the corresponding unconjugated forms. The deoxycholate-induced mucus discharge was not altered by pharmacological blockers (tetrodotoxin, atropine), indomethacin, mast cell stabilizers (ketotifen, doxantrazole), H1 histamine receptor antagonist (pyrilamine), or 5-HT receptor antagonists (ketanserin, ondansetron, SDZ 205-557). Our findings suggest that some bile salts, especially in the unconjugated form, may provoke colonic mucus secretion, probably through a direct action on mucus-secreting cells.

Animals↗
PubMed2001

Effect of resistant starch on potential biomarkers for colonic cancer risk in patients with colonic adenomas: a controlled trial.

Resistant starch decreases the concentration of secondary bile acids in the feces and the proliferation rate of colonic mucosal cells in healthy volunteers. This may reduce the risk of colon cancer. We investigated 23 patients with recently removed colonic adenoma(s) in a controlled parallel trial. They consumed 45 g of maltodextrin per day as placebo for four weeks and were randomly assigned to either 45 g of native amylomaize starch, containing 28 g of resistant starch type II or 45 g of maltodextrin for another four weeks. No effect on colorectal cell proliferation, fecal wet and dry weights, pH, and short-chain fatty acid excretion was seen. The bile acid concentration in fecal water decreased by 15% (P = 0.048) and the percentage secondary bile acids decreased by 14% (P = 0.002) on resistant starch relative to placebo. Whether this has a substantial role in colon cancer prevention in these patients remains to be established.

Adenoma↗
PubMed1993

Comparison of the permeability characteristics of a human colonic epithelial (Caco-2) cell line to colon of rabbit, monkey, and dog intestine and human drug absorption.

The in vitro permeabilities of Caco-2 monolayers and permeabilities in tissue sections from colon of monkey, rabbit, and dog were compared using a series of compounds. The selected compounds differed in their physicochemical properties, such as octanol/water partition coefficient, water solubility, and molecular weight. Their structure included steroids, carboxylic acids, xanthins, alcohols, and polyethylene glycols. A linear permeability relationship was established between Caco-2 and colon tissue from both rabbit and monkey. The results suggest that Caco-2 is twice as permeable as rabbit and five times as permeable as monkey colon. However, no clear relationship could be established between Caco-2 monolayers and dog colon permeability. A relationship between permeability in Caco-2 monolayers and human absorption was found. The results suggest that within certain limits, permeability of Caco-2 monolayers may be used as a predictive tool to estimate human drug absorption.

Animals↗
PubMed2003

Effect of colonic lactulose availability on the timing of drug release onset in vivo from a unique colon-specific drug delivery system (CODES).

PURPOSE: To test the hypothesis that the onset of drug release in vivo from a unique colon-specific drug delivery system (CODES) would depend on the colonic availability rate of lactulose. The site specificity of drug release in canine GI tract was also estimated. METHODS: CODES tablets were prepared by tableting the granulation or acetaminophen and lactulose, followed with film coating. The pharmacokinetic performance of different CODES formulations was evaluated in six beagle dogs under fasted conditions. The release of acetaminophen and lactulose was also characterized in vitro. RESULTS: The onset of acetaminophen release in beagle dogs was found to be dependent on the coating level of Eudragit E and lactulose loading in the core tablet. At Eudragit E coating levels of 4%, 8% and 12% (coating weight gain), the onset of in vivo drug release occurred 5.5 (+/- 1.9) h. 4.8 (+/-1.0) h. and 7.5 (+/-1.0) h, respectively, after dosing. A similar trend was observed when the loading of lactulose in the core tablet decreased from 78% to 58% and 38%. However, the rate and extent of acetaminophen absorption did not vary significantly in each situation based on the values of AUC and Cmax. CONCLUSION: The onset of drug release in vivo from CODES tablets is predominantly dependent on colonic availability rate of lactulose because drug release from this system is triggered by localized drop of colonic pH from the fermentation of lactulose.

Acetaminophen↗
PubMed1999

Modulation of base hydroxylation by bile acids and salicylates in a model of human colonic mucosal DNA: putative implications in colonic cancer.

Bile acids are believed to be involved in the formation of colonic cancer, and 5-aminosalicylic acid and other salicylates may have a protective role. The precise mechanisms of both actions are not known, but modifications (stimulation or inhibition) of basal or oxygen-radical induced DNA base hydroxylation as potential early events in tumor formation by these compounds may be involved in such actions. We, therefore, investigated whether: (1) bile acids in concentrations as they occur systemically or intraluminally are able to enhance basal or OH*-radical-stimulated base hydroxylation in DNA from calf thymus; (2) 5-aminosalicylic acid, its main intestinal metabolite N-acetyl-aminosalicylic acid and salicylate, the main aspirin metabolite, are able to inhibit this hydroxylation; and (3) DNA from calf thymus can be used as a model by comparing its base composition and hydroxylation with DNA from normal human colonic mucosa. We found an enhancement of the OH*-radical-induced DNA hydroxylation especially 8-OH adenine with 214.0%. On the other hand 5-ASA, N-acetyl-ASA, and salicylate showed a concentration-dependent inhibition of OH*-stimulated hydroxylation with IC50 between 0.04 +/- 0.01 mM (X +/- SD) and 1.3 +/- 0.1 mM. No effects were observed on basal hydroxylation. Electron spin resonance spectroscopy studies showed reduction of the corresponding base signals pointing to a scavenger mechanism. In DNA isolated from normal human colonic mucosa (N = 7) a similar base distribution was found as in calf thymus; hydroxylation was < or = 1.0% in both systems. From our results we conclude that DNA from calf thymus may serve as a model for human colonic mucosal DNA and that one of the carcinogenic actions of bile acids may be enhancement of oxygen-radical-induced DNA base hydroxylation, especially 8-OH adenine. The absence of effects under unstimulated conditions supports their role as cocarcinogens. The concentration-dependent inhibition of OH*-stimulated DNA hydroxylation by 5-ASA, salicylate, and N-acetyl-ASA may be a possible mechanism of chemoprevention.

Animals↗
PubMed2002

Differential expression of carcinoembryonic antigen (CEA) splice variants in whole blood of colon cancer patients and healthy volunteers: implication for the detection of circulating colon cancer cells.

Quantification of circulating cancer cells in whole blood samples by real time quantitative RT-PCR might be of clinical value for monitoring therapeutic effectiveness. In colon cancer patients, carcinoembrynic antigen (CEA) and cytokeratin 20 (CK20) have been frequently used for RT-PCR based tumor cell detection, but the specificity in particular for CEA has been questioned. In this study, we compared real-time RT-PCR for CEA and CK20 and analysed patients with metastatic disease (n=32) and healthy volunteers (n=17). CK20 mean values were elevated in cancer patients (P<0.001) and defined a subgroup (38%) who showed CK20 levels at least 100-fold above the highest value of the healthy control group. In contrast, only two cancer patients (6%) showed elevated CEA levels. Samples of the healthy control group showed exclusively a CEA-PCR product of 79 degrees C melting temperature. Thirty per cent of the colon cancer patients showed an additional product of 82 degrees C melting temperature. The 82 degrees C product was identical with the amplification product of CEA-cDNA and cDNA from different colon cancer cell lines. Colon cancer cells were spiked into normal blood in 10-fold dilutions that resulted in a dose dependent shift of the melt curve from 79 degrees C to the 82 degrees C. Sequencing of the PCR products showed that white blood cells express a splice variant of CEA, which hinders detection of tumor cell cDNA in whole blood samples. Our findings have implications for the use of CEA as a diagnostic molecule (e.g. by RT-PCR). The discovery of a physiologically expressed CEA splice variant might lead to a better understanding of the biological function of CEA and its family members.

Adenocarcinoma↗
PubMed2001

Colonic luminal contents induce cyclooxygenase 2 transcription in human colon carcinoma cells.

BACKGROUND & AIMS: Evidence is accumulating that inhibitors of cyclooxygenase (COX)-2 activity are useful for preventing human colon cancer. Therefore, it is important to determine whether agents in the colonic luminal contents can influence the transcriptional regulation of COX-2 in colonic cells. METHODS: Transient transfections were performed, using a human COX-2 promoter-luciferase construct, in HCT 116 cells, and the effects of pure luminal compounds and components of fecal water, the fecal fraction in direct contact with the colonocytes, on luciferase activity studied. RESULTS: The luminal compounds deoxycholate, chenodeoxycholate, and butyrate all induced COX-2 promoter activity in HCT 116 cells. Lipid extracts of human fecal water also induced promoter activity in these cells, and the extent of induction varied between individuals. Induction of COX-2 promoter activity by the lipid extracts was positively correlated with induction of activator protein 1-dependent gene transcription. Results also indicated that protein kinase C and p38 mitogen-activated protein kinase mediated the effect of the luminal agents on COX-2 promoter activity. CONCLUSIONS: Components in the luminal contents can effect COX-2 transcription and may influence colonic tumor development. Available data suggest that the responsible components are under dietary influence.

Butyric Acid↗
PubMed2005

The human colonic monocarboxylate transporter Isoform 1: its potential importance to colonic tissue homeostasis.

BACKGROUND & AIMS: Butyrate serves as the major source of energy for colonic epithelial cells, and has profound effects on their proliferation, differentiation, and apoptosis. Transport of butyrate across the colonocyte luminal membrane is mediated by the monocarboxylate transporter, MCT1; the expression of which is down-regulated dramatically during colon carcinogenesis. We have proposed that the decline in MCT1 expression during colon carcinogenesis may reduce the intracellular availability of butyrate required to regulate expression of genes associated with the processes maintaining tissue homeostasis within the colonic mucosa. METHODS: To test this hypothesis we used the technique of RNA interference to inhibit MCT1 expression specifically, and determined the consequences of this inhibition on the ability of butyrate to exert its recognized effects in vitro using flow cytometry, immunofluorescence, Northern analysis, and Western analysis. RESULTS: We show that inhibition of MCT1 expression, and hence butyrate uptake, has profound inhibitory effects on the ability of butyrate to regulate expression of key target genes: p21waf1/cip1 (p21), intestinal alkaline phosphatase (IAP), and cyclin D1, and their associated processes of proliferation and differentiation. In contrast, inhibition of MCT1 expression had no effect on the ability of butyrate to modulate expression of either bcl-XL or bak, and this was reflected in a corresponding lack of effect on butyrate induction of apoptosis. CONCLUSIONS: Collectively, these results show the importance of MCT1 to the ability of butyrate to induce cell-cycle arrest and differentiation, and suggest fundamental differences in the mechanisms by which butyrate modulates specific aspects of cell function.

Alkaline Phosphatase↗