Lithocholic acid: a new emergent protector of intestinal calcium absorption under oxidant conditions.

LCA and 1,25(OH)2D3 are vitamin D receptor ligands with different binding affinity. The secosteroid stimulates intestinal Ca2+ absorption. Whether LCA alters this process remains unknown. The aim of our work was to determine the effect of LCA on intestinal Ca2+ absorption in the absence or presence of NaDOC, bile acid that inhibits the cation transport. The data show that LCA by itself did not alter intestinal Ca2+ absorption, but prevented the inhibitory effect of NaDOC. The concomitant administration of LCA avoided the reduction of intestinal alkaline phosphatase activity caused by NaDOC. In addition, LCA blocked a decrease caused by NaDOC on gene and protein expression of molecules involved in the transcellular pathway of intestinal Ca2+ absorption. The oxidative stress and apoptosis triggered by NaDOC were abrogated by LCA co-treatment. In conclusion, LCA placed in the intestinal lumen protects intestinal Ca2+ absorption against the inhibitory effects caused by NaDOC. LCA avoids the reduction of the transcellular Ca2+ movement, apparently by blocking the oxidative stress and apoptosis triggered by NaDOC, normalizing the gene and protein expression of molecules involved in Ca2+ movement. Therefore, LCA might become a possible treatment to improve intestinal calcium absorption under oxidant conditions.

17 Beta-estradiol prevents cytotoxicity from hydrophobic bile acids in HepG2 and WRL-68 cell cultures.

BACKGROUND: Epidemiological and clinical studies suggest the possibility that estrogens might have a cytoprotective effect on the liver. The aim of the present study was to test the hypothesis that 17beta-estradiol (E2) prevents hepatocellular damage induced by deoxycholic acid (DCA), a hydrophobic bile acid. METHODS: HepG2 cells were exposed for 24 h to DCA (350 micromol/L). Cell viability, aspartate aminotransferase and lactate dehydrogenase activity and apoptosis were measured as indices of cell toxicity. The effect of DCA was compared to that observed using either a hydrophilic bile acid, ursodeoxycholic acid (UDCA; 100 micromol/L), or E2 at different concentrations (1 nmol/L, 10 nmol/L, 50 nmol/L and 50 micromol/L) or mixtures of E2/DCA or UDCA/DCA. The same experiments were performed using WRL-68 cells that, at variance with HepG2, express a higher level of nuclear estrogen receptor. RESULTS: High concentrations of E2 and UDCA prevented DCA-induced decrease in cell viability, increase in enzyme activity and apoptosis evaluated both by 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) and TdT-mediated dUTP nick-end labeling (TUNEL) assays. In addition, DCA-related apoptosis, assessed by caspase activity, was also prevented by E2 (P < 0.01) in physiological (1-10 nmol/L) doses. The cytoprotective effects of E2 and UDCA was also observed in the WRL-68 cell line. CONCLUSIONS: 17Beta-Estradiol prevents DCA-induced cell damage in HepG2 and WRL-68 cell lines to an extent comparable to UDCA. The hypothesis that the protective effect of E2 may be mediated by a mechanism that is nuclear estrogen receptor independent, deserves further verification.

Chronic but not acute conjugated linoleic acid treatment inhibits deoxycholic acid-induced protein kinase C and nuclear factor-kappaB activation in human colorectal cancer cells.

Conjugated linoleic acid (CLA) has anti-carcinogenic effects in a variety of cancers including colon cancer. Secondary bile acids on the other hand are known as tumour promoters in colon cancer with effects on protein kinase C (PKC) and nuclear factor kappa B (NF-kappaB) signalling pathways. The aim of this study was to examine acute and chronic, isomer-specific effects of CLA on bile salt-induced PKC and NF-kappaB signal transduction in human colon cancer cells. HCT116 cells were treated with 100 mumol/l and 50 mumol/l cis-9,trans-11-CLA and trans-10,cis-12-CLA for 24 h and 14 days, respectively. The cells were then transfected with DNA coding for PKC beta1-EGFP (enhanced green fluorescent protein), PKC delta-EGFP or PKC zeta-EGFP fusion protein and activated with deoxycholic acid (DCA), phorbol myristate acetate (PMA) or C2-ceramide. PKC translocation was observed using real-time photomicroscopy and fluorescent microscopy and NF-kappaB analyses by gel shift assays. Chronic c-9,t-11-CLA and t-10,c-12-CLA treatment inhibited DCA-induced PKC beta1 and PKC delta translocation and also inhibited NF-kappaB activation. Acute CLA treatment had no effect on PKC or NF-kappaB activation. In conclusion this study indicates that chronic CLA treatment inhibits DCA-induced PKC and NF-kappaB activation in colon cancer cells. These data suggest mechanisms by which CLA may influence the course of colonic cancer.

Ursodeoxycholic acid inhibits interleukin 1 beta [corrected] and deoxycholic acid-induced activation of NF-kappaB and AP-1 in human colon cancer cells.

Deoxycholic acid (DCA) has been implicated in colorectal carcinogenesis in humans with effects on proliferation and apoptosis, mediated at least in part by activation of transcription factors nuclear factor kappa B (NF-kappaB), activator protein 1 (AP-1) and protein kinase C (PKC) enzymes. Ursodeoxycholic acid (UDCA) is reported to reduce the frequency of colonic carcinogenesis in ulcerative colitis patients. Hence, we postulated that it might differ from DCA in its regulation of these transcription factors. The aim of the study was to determine effects of DCA and UDCA on NF-kappaB and AP-1 activation and explore its relationship to PKC. Human colonic tumour cell lines HCT116 were treated with DCA, UDCA, alone or pretreated with UDCA followed by DCA or IL-1beta. In other experiments, cells were pretreated with PKC inhibitors and then stimulated with DCA and IL-1beta or PMA. Gel shift assays were performed on nuclear extracts of the cells for NF-kappaB and AP-1 analysis. Western blot analyses and immunofluorescence were performed for Rel A (p65) and IkappaB-alpha levels on the treated cells. DCA increased NF-kappaB and AP-1 DNA binding. UDCA did not increase DNA binding of NF-kappaB and AP-1 and UDCA pretreatment inhibited DCA-induced NF-kappaB and AP-1 DNA binding. PKC inhibitors blocked DCA-induced NF-kappaB and AP-1 activation. These results were validated by Western blot analysis for RelA and IkappaB-alpha. In conclusion, UDCA did not induce NF-kappaB and AP-1 DNA binding but also blocked DCA-induced NF-kappaB and AP-1 activation. These findings suggest a possible mechanistic role for UDCA in blocking pathways thought to be involved in colon carcinogenesis.

Characteristics of apoptosis in HCT116 colon cancer cells induced by deoxycholic acid.

Hydrophobic bile acids induce apoptosis in both colon cancer cells and hepatocytes. The mechanism by which colon cancer cells respond to bile acids is thought to be different from that of hepatocytes. Therefore, we investigated the characteristics of apoptosis in colon cancer cell line HCT116. Hydrophobic bile acids, i.e., deoxycholic acid (DCA), and chenodeoxycholic acid, induced apoptosis in HCT116 cells. Apoptotic indications were detectable at as early as 30 min and the extent increased in time- and concentration-dependent manners. SDS and a hydrophilic bile acid, cholic acid, did not induce apoptosis even at cytotoxic concentrations. Pretreatment with cycloheximide failed to inhibit apoptosis, suggesting that protein synthesis is not involved in the apoptotic response. Release of cytochrome c from mitochondria and activation of caspase-9 were detectable after 5 and 10 min, respectively, whereas remarkable activation of Bid was not detected. Ursodeoxycholic acid (UDCA) protected HCT116 cells from DCA-induced apoptosis but a preincubation period of > or =5 h was required. Nevertheless, UDCA did not inhibit cytochrome c release from mitochondria. Our results indicate that hydrophobic bile acids induce apoptosis in HCT116 cells by releasing cytochrome c from mitochondria via an undefined but specific mechanism, and that UDCA protects HCT116 cells by acting downstream of cytochrome c release.

Deoxycholic acid inhibits pacemaker currents by activating ATP-dependent K+ channels through prostaglandin E2 in interstitial cells of Cajal from the murine small intestine.

1. We investigated the role of deoxycholic acid in pacemaker currents using whole-cell patch-clamp techniques at 30 degrees C in cultured interstitial cells of Cajal (ICC) from murine small intestine. 2. The treatment of ICC with deoxycholic acid resulted in a decrease in the frequency and amplitude of pacemaker currents and increases in resting outward currents. Also, under current clamping, deoxycholic acid produced the hyperpolarization of membrane potential and decreased the amplitude of the pacemaker potentials. 3. These observed effects of deoxycholic acid on pacemaker currents and pacemaker potentials were completely suppressed by glibenclamide, an ATP-sensitive K(+) channel blocker. 4. NS-398, a specific cyclooxygenase-2 (COX-2) inhibitor, significantly inhibited the deoxycholic acid-induced effects. The treatment with prostaglandin E(2) (PGE(2)) led to a decrease in the amplitude and frequency of pacemaker currents and to an increase in resting outward currents, and these observed effects of PGE(2) were blocked by glibenclamide. 5. We next examined the role of deoxycholic acid in the production of PGE(2) in ICC, and found that deoxycholic acid increased PGE(2) production through the induction of COX-2 enzyme activity and its gene expression. 6. The results suggest that deoxycholic acid inhibits the pacemaker currents of ICC by activating ATP-sensitive K(+) channels through the production of PGE(2).

Ursodeoxycholic acid (UDCA) can inhibit deoxycholic acid (DCA)-induced apoptosis via modulation of EGFR/Raf-1/ERK signaling in human colon cancer cells.

Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, is known as a cytoprotective agent. UDCA prevents apoptosis induced by a variety of stress stimuli including cytotoxic bile acids such as deoxycholic acid (DCA). Here we examined the molecular mechanism by which UDCA can antagonize DCA-induced apoptosis in human colon cancer cells. UDCA pretreatment decreases the number of apoptotic cells caused by exposure to DCA and UDCA. Further studies of the signaling pathway showed that UDCA pretreatment suppressed DNA binding activity of activator protein-1 and this was accompanied by downregulation of both extracellular signal-regulated kinase (ERK) and Raf-1 kinase activities stimulated by exposure to DCA. DCA was also found to activate epidermal growth factor receptor (EGFR) activity and UDCA inhibited this. Collectively, these findings suggest that the inhibitory effect of UDCA in DCA-induced apoptosis is partly mediated by modulation of EGFR/Raf-1/ERK signaling.

Comparative cytotoxic and cytoprotective effects of taurohyodeoxycholic acid (THDCA) and tauroursodeoxycholic acid (TUDCA) in HepG2 cell line.

This study was performed to compare the effects of two hydrophilic bile acids, taurohyodeoxycholic acid (THDCA) and tauroursodeoxycholic acid (TUDCA), on HepG2 cells. Cytotoxicity was evaluated at different times of exposure by incubating cells with increasing concentrations (50-800 micromol/l) of either bile acid, while their cytoprotective effect was tested in comparison with deoxycholic acid (DCA) (350 micromol/l and 750 micromol/l)-induced cytotoxicity. Culture media, harvested at the end of each incubation period, were analyzed to evaluate aspartate transaminase (AST), alanine transaminase and gamma-glutamyltranspeptidase release. In addition, the hemolytic effect of THDCA and TUDCA on human red blood cells was also determined. At 24 h of incubation neither THDCA nor TUDCA was cytotoxic at concentrations up to 200 and 400 micromol/l. At 800 micromol/l both THDCA and TUDCA induced a slight increase in AST release. At this concentration and with time of exposure prolonged up to 72 h, THDCA and TUDCA induced a progressive increase of AST release significantly (P<0.05) higher than that of controls being AST values for THDCA (2.97+/-0.88 time control value (tcv) at 48 h and 4.50+/-1.13 tcv at 72 h) significantly greater than those of TUDCA (1.50+/-0.20 tcv at 48 h and 1.80+/-0.43 tcv at 72 h) (P<0.01). In cytoprotection experiments, the addition of 50 micromol/l THDCA decreased only slightly (-5%) AST release induced by 350 micromol/l DCA, while the addition of 50 micromol/l TUDCA was significantly effective (-23%; P<0.05). Higher doses of THDCA or TUDCA did not reduce toxicity induced by 350 micromol/l DCA, but were much less toxic than an equimolar dose of DCA alone. At the concentration used in this experimental model neither THDCA nor TUDCA was hemolytic; however at a very high concentration (6 mmol/l) both bile acids induced 5-8% hemolysis. We conclude that bile acid molecules with a similar degree of hydrophilicity may show different cytotoxic and cytoprotective properties.

Lowering of sodium deoxycholate-induced nasal ciliotoxicity with cyclodextrins.

AIM: To lower the nasal ciliotoxicity of sodium deoxycholate (SDC) in combination with cyclodextrins (CD). METHODS: The erythrocyte hemolysis test was carried out to evaluate the damaging effect of SDC on the erythrocyte membrane. The in situ toad palate model and scanning electron microscope technique were used to investigate the nasal ciliotoxicity of SDC solution in combination with CD. The inclusion effect between SDC and beta-cyclodextrin (beta-CD) was studied by differential thermal analysis (DTA) and X-ray diffractometry. RESULTS: The hemolysis test showed that beta-CD and dimethyl-beta-cyclodextrin (DM-beta-CD) could effectively protect the erythrocyte membrane against damage by SDC at the molar ratios of 1:1 and 2:1. When SDC combined with beta-CD or DM-beta-CD at a molar ratio of 1:2 or 1:3, the ciliotoxicity of SDC was greatly alleviated and the percent lasting time of the ciliary movement increased to 50 % or above. Scanning electron microscope investigations showed that SDC combined with beta-CD at a molar ratio 1:2 had no marked damage on the rat nasal mucosa after nasal administration thrice a day for a week. DTA and X-ray diffractometry investigations showed that SDC formed an inclusion with beta-CD. CONCLUSION: Combining beta-CD or DM-beta-CD with SDC can greatly lower the hemolytic effect and ciliotoxicity of SDC and the optimal molar ratio of SDC to CD is 1:2. Such protection provided by CD is due to the inclusion effect between SDC and CD.

Soybean resistant proteins interrupt an enterohepatic circulation of bile acids and suppress liver tumorigenesis induced by azoxymethane and dietary deoxycholate in rats.

We found that azoxymethane and dietary deoxycholate induced liver tumors in rats. The incidence and the development of the tumor were closely related to the enterohepatic circulation of bile acids. The feeding of a high-molecular-weight fraction of soy protein digest (HMF) suppressed the tumorigenesis, probably due to the inhibitory effect of soybean resistant protein on reabsorption of bile acids in the intestine.

Effect of deoxycholic acid and ursodeoxycholic acid on lipid peroxidation in cultured macrophages.

BACKGROUND: Kupffer cells are essential for normal hepatic homeostasis and when stimulated, they secrete reactive oxygen species, nitric oxide, eicosanoids, and cytokines. Some of these products are cytotoxic and attack nucleic acids, thiol proteins, or membrane lipids causing lipid peroxidation. Hydrophobic bile acids, such as deoxycholic acid (DCA), can damage hepatocytes by solubilising membranes and impairing mitochondrial function, as well as increasing the generation of reactive oxygen species. OBJECTIVES: The hypothesis that hydrophobic bile acids could stimulate Kupffer cells to increase their capacity to generate reactive oxygen species by measuring cellular lipid peroxidation was tested. Because the hydrophilic bile acid, ursodeoxycholic acid (UDCA) can block hydrophobic bile acid induced cellular phenomena, it was also hypothesised that UDCA could antagonise macrophage activation by hydrophobic bile acids to blunt their capacity to generate reactive oxygen species. METHODS: J-774A.1 murine macrophages were incubated for 24 hours with either 10(-5) M and 10(-4) M (final concentration) DCA alone, or 10(-4) M UDCA alone, or a mixture of 10(-4) M 1:1 molar ratio of DCA and UDCA. At the end of the incubation period, the culture medium was collected for determination of cellular lipid peroxidation by measuring the malondialdehyde (MDA) content in the medium with the thiobarbituric acid reactive substances assay. RESULTS: 10(-5) M and 10(-4) M DCA increased MDA generation by cultured macrophages. 10(-4) M UDCA alone did not increase MDA generation but blocked the peroxidative actions of DCA. CONCLUSIONS: Hydrophobic bile acids, after their hepatic retention, can oxidatively activate Kupffer cells to generate reactive oxygen species. Because UDCA can block this action, the beneficial effect of UDCA is, in part, related to its ability to act as an antioxidant.

Effects of gomisin A on the promotor action and serum bile acid concentration in hepatocarcinogenesis induced by 3'-methyl-4-dimethylamino-azobenzene.

The effects of gomisin A, a lignan component of Schizandra fruits, on the promotion stage of hepatocarcinogenesis initiated by 3'-methyl-4-dimethylamino-azobenzene (3'-MeDAB) in male Donryu rats were investigated. When different types of tumor promotors, phenobarbital (PB) and deoxycholic acid (DCA), were administered for 5 weeks after initiation by 3'-MeDAB, preneoplastic alterations in the liver, determined by glutathione S-transferase placental form (GST-P), were markedly increased. Gomisin A significantly inhibited the increase in number and size of GST-P positive foci, regardless of the promotor. This lignan inhibited the increase in serum bile acid concentration by administration of DCA, but hardly influenced the serum bile acids in the PB-combined group. These results suggest that the inhibitory effect of gomisin A on the promotive action of DCA is based on improving bile acid metabolism, but regarding the action of PB, the effect could not be elucidated from the metabolism of bile acids.

Antagonistic effects of deoxycholic acid and butyrate on epithelial cell proliferation in the proximal and distal human colon.

Colon cancer is a major malignant disease in Western countries where--for unknown reasons--it occurs predominantly in the distal colon. Fecal secondary bile acids are an important risk factor whereas butyrate may be a protective agent. In this in-vitro study biopsies from the normal ascending and sigmoid colon of 24 subjects were incubated with 5 microM DCA (proximal vs. sigmoid colon) or DCA and DCA plus 10 mM butyrate (DCA vs. DCA/BUT, only sigmoid colon) and cell proliferation measured by bromodeoxyuridine immunohistochemistry. Whole crypt labeling index (LI) after DCA-incubation was similar in the ascending (15.4%) and sigmoid colon (15.4%) indicating an equal mucosal response of the two colonic subsites to DCA. Compared to DCA/BUT, incubation with DCA alone resulted in a significantly higher LI for the whole crypt (16.8 vs. 11.4%, p < 0.01) and for the upper 40% of the crypt (4.5 vs. 0.8%, p < 0.01). This may indicate a butyrate-related decrease in the susceptibility for colon cancer. Since luminal concentrations of DCA and butyrate are influenced by dietary interventions the findings of this study may be of particular interest with regard to colon cancer development and prevention.

Calcium, vitamin D, and colon cancer.

Calcium contributes to the progression of epithelial cells through all phases of the proliferative cycle and into stages of cell differentiation; intracellular concentrations of calcium that are required for cell renewal, however, are lower than those required for epithelial-cell differentiation. These effects of calcium are modulated by interactions with 1,25-dihydroxy-vitamin D3, phosphate, and fatty acids, all of which are partly dependent on dietary intake. In rodent models, increased dietary calcium inhibited hyperproliferation of colon epithelial cells induced by increased levels of fatty acids or bile acids present in the colon. When carcinogens induced hyperproliferation of colon epithelial cells the hyperproliferation was decreased by added dietary calcium, and in several animal models the occurrence of carcinogen-induced carcinomas of the colon decreased with increased dietary calcium. A nutritional stress diet, designed to represent human Western dietary intake of calcium, phosphate, vitamin D, and fat, produced hyperproliferation and hyperplasia in the colons of rodents; these effects were reduced by increasing dietary levels of calcium. Decreased levels of ornithine decarboxylase also were reported in human and rodent colon mucosa exposed to increasing levels of calcium. In human subjects at increased risk for familial colon cancer, hyperproliferation of colon epithelial cells was reduced after oral dietary supplementation with calcium. In epidemiological studies, several investigators reported inverse correlations between levels of dietary calcium intake and the incidence of colon cancer. Extrapolation of the data have suggested a protective effect of total calcium intakes above 1500 to 1800 mg/day.

E-3123, a new synthetic protease inhibitor, protects against deoxycholic acid-induced acute pancreatitis in dogs.

The effects of intravenous infusion of 4-(2-succinimidoethylthio)phenyl 4-guanidinobenzoate (E-3123), a new synthetic protease inhibitor, on deoxycholic acid-induced acute pancreatitis in a canine pancreas were investigated. The retrograde injection of 1% deoxycholic acid into the pancreatic duct significantly and time-dependently increased venous serum amylase and lipase activities. E-3123 significantly decreased these increased amylase and lipase activities. Two hours after deoxycholic acid injection, the amylase activity was reduced by 23 +/- 3% and 34 +/- 4% after infusion of 0.1 and 1 mg/kg/hr of E-3123, respectively, compared to the corresponding values in the control group, and the lipase activity was reduced by 13 +/- 3% and 29 +/- 3%, respectively. The potency of 1 mg of E-3123 to decrease these enzymes was almost the same as that of 5 mg of gabexate, a novel protease inhibitor. Pancreatic wet weight/body weight also decreased after treatment with E-3123 in dogs injected with deoxycholic acid. Histologic examination revealed that injection with deoxycholic acid caused marked interstitial edema, hemorrhage, vacuolization and inflammation as well as focal acinar cell necrosis, while in the E-3123-treated group, only mild changes in these parameters were seen. These results suggest that E-3123 may be useful in suppressing the progression of acute pancreatitis induced by deoxycholic acid, at least in part, through its protease-inhibiting ability.

Injury induced by fatty acids or bile acid in isolated human colonocytes prevented by calcium.

Measurement of the modulation of the growth fraction of isolated normal colonocytes from adult subjects in primary monolayer culture was used as a sensitive quantitative assay to evaluate toxic effects of several endogenous compounds found within the colon. This assay was used to study the role of CaCl2 in blocking cell injury. When added simultaneously with the injurious agent, 5-10 mM CaCl2 blocked the toxicity of physiological concentrations of deoxycholic acid, oleic acid, palmitic acid and linoleic acid.

Colon cancer and dietary fiber: cellulose inhibits the DNA-damaging ability of bile acids.

Colon cancer is the second most common type of cancer in the United States. Bile acids have been implicated in the etiology of this disease. In a previous study, we showed that bile acids can damage DNA in vitro. In this study, we report that this damage is largely prevented when the bile acids are pretreated with cellulose fiber. Preliminary data show that cellulose may act as a catalyst to promote polyesterification of bile acid to a biologically inactive form.

The tropic effect of intrarectal deoxycholate on rat colorectum is unaffected by oral metronidazole.

Intrarectal administration of sodium deoxycholate (SDC) enhances experimental colorectal carcinogenesis, an effect that is partly vitiated by oral metronidazole. The effect of topical SDC with or without concurrent metronidazole on colorectal cell proliferation was explored in male Sprague-Dawley rats (n = 30) allocated to five groups. Two groups received thrice weekly intrarectal instillations of 1 ml N saline or 1 ml 0.12 M SDC. A third group received SDC plus metronidazole 22.5 mg/kg/day in the drinking water. Controls had no instillations or metronidazole alone. At time of killing (10 weeks), crypt cell production rate (CCPR) was determined by the stathmokinetic technique for four large-bowel segments. Saline had no significant effect on colorectal CCPR but SDC produced increases throughout, varying from 53% in the proximal colon to 222% in the rectum (P less than 0.01). Metronidazole did not reduce this effect, although given alone it reduced colonic CCPR by 40 to 50%. The direct tropic effect of bile acids could largely explain their cocarcinogenic properties. Since metronidazole does not prevent this increase in cell proliferation, its mildly protective role against cancer may reflect the presence of fewer anaerobes capable of degrading bile acids to carcinogenic metabolites.

Prostaglandin E2 counteracts the inhibition by indomethacin of rat colon ornithine decarboxylase induction by deoxycholic acid.

The mechanism whereby bile acids promote colon tumor development was studied. Bile acids increase intestinal ornithine decarboxylase (ODC), an effect that is suppressed by indomethacin, an inhibitor of prostaglandin (PG) synthesis. Male Sprague-Dawley rats were pretreated with 0.002% indomethacin solution in drinking water for 3 days, then given a single intrarectal instillation of 20 mg of deoxycholate and/or 1 mg of PGE2. Four hours later, the rats were killed, and the ODC activity was measured in the mucosa of the distal large bowel. ODC was significantly lower in rats given indomethacin plus deoxycholate than in those given deoxycholate alone, but it was significantly higher in rats treated with indomethacin and PGE2 plus deoxycholate. Without deoxycholate, indomethacin plus PGE2 did not elevate ODC compared with indomethacin alone or no treatment. Indomethacin reduced the colonic mucosal PG level. Thus, PGE2 mediates the deoxycholate-induced colonic mucosal ODC activity, and overcomes the inhibition of this enzyme activity by indomethacin. It is concluded that the anti-promoting effect of indomethacin in colon carcinogenesis, previously demonstrated, may result from the indomethacin inhibition of PG synthesis.

Inhibition by loperamide of deoxycholic acid induced intestinal secretion.

The effect of loperamide on deoxycholic acid (DOC)-induced secretion was studied in ligated loops of the rat jejunum and colon in vivo. In controls, loperamide slightly augmented fluid absorption. 3 mmol DOC caused net fluid secretion. Loperamide reduced this secretion in the colon and reversed it to absorption in the jejunum. Na-K-ATPase specific activity and cAMP levels were measured in the jejunum, and [14C]erythritol clearance as an index of mucosal permeability in the colon. In the jejunum this opiate analogue affected neither basal or DOC-depressed Na-K-ATPase, nor mucosal cAMP. In the colon it reduced a large increase of the erythritol clearance caused by DOC. It is suggested that loperamide interferes with DOC-induced intestinal secretion in part by lowering mucosal permeability.