deoxycholic-acid and Adenoma

Topics: Adenoma; Animals; Cell Division; Cell Line; Cells, Cultured; Colonic Neoplasms; Culture Techniques; Deoxycholic Acid; Epidermal Growth Factor; Humans; Models, Biological; Plasminogen Activators; Precancerous Conditions; Tetradecanoylphorbol Acetate

To assess whether deoxycholic acid (DOC) and lithocholic acid (LCA) administered in a period of six months in a concentration of 0.25% may have a carcinogenic role in mice colon.. The study used C57BL6 female mice divided into four groups. The control group received a balanced diet and the others received diets supplemented with 0.25% DOC, 0.25% LCA and 0.125% DOC+0.125% LCA, respectively. After euthanasia, the lesions found in the resected gastrointestinal tracts were stained with hematoxylin-eosin and examined microscopically.. No gastrointestinal tract changes were observed in the control group, while hyperplastic Peyer's patches in the small intestine, flat adenomas with mild dysplasia and chronic colitis at the level of the colon were found in all three test groups. The colonic lesions prevailed in the proximal colon. The highest number of flat adenoma lesions (8), hyperplasia of Peyer's patches (25) and chronic colitis (2) were found in mice fed with diet and LCA.. Precancerous or cancerous pathological lesions could not be identified. Instead, adenomatous colonic injuries occurred in a shorter period of time (six months), compared to the reported data.

Topics: Adenoma; Animals; Bile Acids and Salts; Carcinogenicity Tests; Carcinogens; Cholagogues and Choleretics; Colitis; Colon; Colonic Neoplasms; Deoxycholic Acid; Disease Models, Animal; Feces; Female; Lithocholic Acid; Mice, Inbred C57BL; Peyer's Patches; Time Factors

Colorectal cancer is one of the leading causes of cancer deaths. It correlates to a high fat diet, which causes an increase of the secondary bile acids including deoxycholate (DOC) in the intestine. We aimed to determine the effects of DOC on intestinal carcinogenesis in Apc (min/+) mice, a model of spontaneous intestinal adenomas. Four-week old Apc (min/+) mice were treated with 0.2 % DOC in drinking water for 12 weeks. The number and size of tumors were measured, and tissue sections were prepared for the evaluation of intestinal carcinogenesis, cell proliferation, and apoptosis. The activation of Wnt signaling was detected in the intestinal tumor cells of the Apc (min/+) mice, and also in the human colon samples. DOC increased the number of intestine tumors by 165.1 % compared with that in untreated Apc (min/+) mice mainly in the middle and distal segments of the small intestine and colon. The numbers of all sizes of tumors in the small intestine were increased. Intestinal carcinogenesis was confirmed in 75 % mice in DOC treated-Apc (min/+) mice compared with 0 % in untreated mice. This was accompanied by promoting tumor cell proliferation and decreasing apoptosis, and increasing the percentage of β-catenin positive cells and its nuclear expression in intestinal tumor cells of Apc (min/+) mice, and also up-regulating the expression of cyclin D1. In addition, the activation of Wnt signaling also played in modulating human colon carcinogenesis. Our studies suggest that DOC enhances the multiplicity of intestinal tumor, and accelerates intestinal adenoma-adenocarcinoma sequence in Apc (min/+) mice mediated by stimulating tumor cell proliferation and decreasing apoptosis through enhancing Wnt signaling.

Topics: Adenocarcinoma; Adenoma; Animals; Blotting, Western; Colorectal Neoplasms; Deoxycholic Acid; Disease Models, Animal; Disease Progression; Genes, APC; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Wnt Signaling Pathway

Topics: Adenoma; Animals; Cholagogues and Choleretics; Colon; Colonic Neoplasms; Deoxycholic Acid; Dietary Supplements; Mice; Mice, Inbred C57BL

LT97 human colonic adenoma cells reflecting early premalignant genotype and growth characteristics have been posed to tumor promoting bile acids in order to identify marker genes that permit identification of tumor promoters in vitro. Physiologically relevant concentrations of desoxycholate (DOC) and chenodesoxycholate (CDC) upregulated expression of c-fos and COX-2 in a concentration- and time-dependent manner. Transient induction of c-fos was seen with the non-promoting taurodesoxycholate (TDOC) as well as DOC, however extended induction at 3 h was only achieved by DOC and CDC reaching 3-6-fold as compared to the control. Stimulation of COX-2 expression was completely specific for the tumor promoting analogs DOC and CDC. It was about 4-fold in the 80 microM DOC and CDC groups after 3 h and increased to 12- and 7-fold respectively after 6 h. Expression of VEGF was stimulated 4-5-fold in the tumor promoter (DOC and CDC) groups and about 2-fold in the non-promoting controls TDOC and GCDC. At later times the tumor promoter specific difference was lost. Our results show that all three genes are modulated in a tumor promoter dependent way and that their upregulation in LT97 adenoma cells can be used for in vitro testing of colon tumor promoters and chemopreventive compounds.

Topics: Adenoma; Bile Acids and Salts; Biomarkers, Tumor; Cell Line, Tumor; Chenodeoxycholic Acid; Colonic Neoplasms; Cyclooxygenase 2; Deoxycholic Acid; Dose-Response Relationship, Drug; Gene Amplification; Gene Expression Regulation, Neoplastic; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Isoenzymes; Membrane Proteins; Polymerase Chain Reaction; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins c-fos; RNA; Taurodeoxycholic Acid; Time Factors; Tumor Necrosis Factor-alpha; Up-Regulation; Vascular Endothelial Growth Factor A

Deoxycholic acid induced programmed cell death and an imbalance with cell proliferation may favour colorectal tumourigenesis according to 'in vitro' studies, but information is lacking on the relationships occurring 'in vivo' in humans.. To evaluate whether serum deoxycholic acid is associated with programmed cell death and cell proliferation in colonic mucosa.. In 10 patients with colorectal adenomas, we measured fasting serum levels of bile acids; and, in normal colonic mucosa, programmed cell death by the TUNEL technique and cell proliferation by immunohistochemical staining with anti-Ki67. Total and compartmental indices for both activities were calculated.. Among serum bile acids, only total deoxycholic acid (median: 0.89 micromol/L +/- 0.54 95% CI), showed a significant positive correlation with the total and basal compartments PCD Index (r = 0.68, p < 0.05). Total proliferation index showed no correlation with either total PCD Index, or bile acids. Within the median compartment of the crypt, cell proliferation was negatively associated with all unconjugated bile acids.. The positive association between deoxycholic acid and programmed cell death in the basal compartment of the crypt, and the negative association of cell proliferation and unconjugated bile acids in the median compartment, do not seem to support the co-carcinogenic effect of deoxycholic acid.

Topics: Adenoma; Aged; Antibodies, Antinuclear; Antibodies, Monoclonal; Apoptosis; Bile Acids and Salts; Cell Proliferation; Colorectal Neoplasms; Deoxycholic Acid; Female; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Intestinal Mucosa; Ki-67 Antigen; Male; Middle Aged

Butyrate has an antitumorigenic effect on colorectal cancer cell lines. Dietary sodium gluconate (GNA) promotes butyrate production in the large intestine. Accordingly, we examined the effect of dietary GNA on tumorigenesis in the large intestine in rats. Male Fisher-344 rats (n = 32) were divided into 4 groups: 2 diets (with or without 50 g GNA/kg basal diet) x 2 treatments (with or without carcinogen administration). Colonic tumors were induced by 3 intraperitoneal injections of azoxymethane (15 mg/kg body wt, 1 time/wk) and dietary deoxycholic acid (2 g/kg basal diet). The experiment was conducted for 33 wk except for a few rats. Ingestion of GNA increased cecal butyrate concentration at the end of experiment (P < 0.01). No tumor development occurred in the untreated groups. Ingestion of GNA decreased the incidence of tumors in rats administered the carcinogen (37.5 vs. 100%, P < 0.05). Ingestion of GNA also decreased the mean number of tumors per rat (0.5 +/- 0.8 vs. 2.8 +/- 1.5, P < 0.01). beta-Catenin accumulation and TdT-mediated dUTP nick end labeling (TUNEL) positive cells in tumors were histochemically examined. The results of this study suggested that the antitumorigenic effect of GNA may involve the stimulation of apoptosis through enhanced butyrate production in the large intestine.

Topics: Adenocarcinoma; Adenoma; Animals; Apoptosis; Azoxymethane; beta Catenin; Butyrates; Carcinogens; Cecum; Colon; Colorectal Neoplasms; Cytoskeletal Proteins; Deoxycholic Acid; Diet; Gluconates; Immunohistochemistry; In Situ Nick-End Labeling; Intestines; Male; Organ Size; Rats; Rats, Inbred F344; Trans-Activators

Aberrant crypt foci, precursors of colonic adenoma, are frequently positive for glutathione-S-transferase P1-1. Because deoxycholic acid is an apoptosis-inducing xenobiotic in the colon, we examined the possibility that aberrant crypt foci, through the cytoprotecting function of glutathione-S-transferase P1-1, resist deoxycholic acid-induced apoptosis, thereby surviving to become adenomas and subsequently cancer.. Glutathione-S-transferase P1-1 or cyclooxygenase-2 expression and the percentage of apoptotic cells in aberrant crypt foci were examined by immunohistochemistry and by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, respectively. Glutathione-S-transferase P1-1 was transfected into colon cancer cells (M7609) and human lung fibroblasts, and deoxycholic acid-induced apoptosis was evaluated by a dye-uptake assay and flow cytometry. Binding of deoxycholic acid to glutathione-S-transferase P1-1 was analyzed by circular dichroism and immunoprecipitation. Caspase activities were determined by colorimetric protease assay, and sulindac binding to glutathione-S-transferase P1-1 was determined by inhibition assay of glutathione-S-transferase P1-1 activity.. Aberrant crypt foci showed positive immunostaining for glutathione-S-transferase P1-1 but negative staining for cyclooxygenase-2. The percentage of apoptotic cells in aberrant crypt foci was significantly lower than in healthy epithelium, and the difference became more apparent with deoxycholic acid treatment. The impaired sensitivity of aberrant crypt foci to deoxycholic acid was restored by the glutathione-S-transferase P1-1-specific inhibitor gamma-glutamyl-S-(benzyl)cysteinyl-R-phenylglycine diethylester. By transfection of glutathione-S-transferase P1-1, M7609 cells became more resistant to deoxycholic acid-induced apoptosis than mock transfectants. Direct binding of glutathione-S-transferase P1-1 to deoxycholic acid was proven by circular dichroism and by immunoprecipitation. The aberrant crypt foci in adenoma patients treated with sulindac, which was shown to bind to glutathione-S-transferase P1-1, underwent apoptosis in 4 days and mostly regressed in 2-3 months.. Glutathione-S-transferase P1-1 protects aberrant crypt foci from deoxycholic acid-induced apoptosis and may play a pivotal role in early colon carcinogenesis.

Topics: Adenoma; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Colonic Neoplasms; Cyclooxygenase 2; Deoxycholic Acid; Detergents; Enzyme Inhibitors; Fibroblasts; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glutathione; Glutathione Transferase; Humans; Intestinal Mucosa; Isoenzymes; Lung; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; RNA, Messenger; Sulindac; Transfection

Butyrate is produced in the colon by fermentation of dietary fibre and induces apoptosis in colon adenoma and cancer cell lines, which may contribute to the protective effect of a high fibre diet against colorectal cancer (CRC). However, butyrate is present in the colon together with unconjugated bile acids, which are tumour promoters in the colon. We show here that bile acids deoxycholate (DCA) and chenodeoxycholate (CDCA), at levels present in the colon, gave a modest increase in cell proliferation and decreased spontaneous apoptosis in AA/C1 adenoma cells. Bile acids significantly inhibited the induction of apoptosis by butyrate in AA/C1 cells. However, the survival-inducing effects of bile acids on AA/C1 cells could be overcome by increasing the concentration of sodium butyrate. These results suggest that dysregulation of apoptosis in colonic epithelial cells by dietary factors is a key factor in the pathophysiology of CRC.

Topics: Adenoma; Apoptosis; Bile Acids and Salts; Butyrates; Cell Division; Cell Survival; Chenodeoxycholic Acid; Colorectal Neoplasms; Deoxycholic Acid; Dietary Fiber; DNA; Dose-Response Relationship, Drug; Humans; Time Factors; Tumor Cells, Cultured

Hyperproliferation of the colorectal mucosa is regarded as an early step in colorectal carcinogenesis. Deoxycholic acid, a secondary bile acid, stimulates colorectal epithelial proliferation in animals and is considered a tumor promoter in human colorectal carcinogenesis. The aim of this study was to investigate the correlation between colorectal mucosal proliferation and the serum deoxycholic acid level.. From each of 19 patients (10 men and 9 women) with (n = 3) or without (n = 16) colorectal adenoma, 18 biopsy specimens were obtained by colonoscopy, 3 from each of the 6 colonic segments. A crude nuclei fraction was prepared, and DNA was stained by propidium iodide to determine the proliferative index (the percentage of cells in the S and G2/M phases of the cell cycle) by flow cytometry. Serum levels of deoxycholic acid were determined by gas-liquid chromatography.. The colonic proliferation rates (median of the values obtained in all segments, 14.1%; range, 10.0-18.7%) and the fasting serum deoxycholic acid levels (median, 0.86 micromol/L; range, 0.28-1.58 micromol/L) showed a significant correlation (r = 0.51, P = 0.03). Serum lithocholic, cholic, chenodeoxycholic, and ursodeoxycholic acid levels were not correlated with the proliferation rates.. Levels of deoxycholic acid in serum are correlated with the rates of the colorectal mucosa. These results are consistent with the concept that deoxycholic acid promotes colorectal carcinogenesis.

Topics: Adenoma; Adult; Bile Acids and Salts; Biomarkers; Carcinogens; Cell Division; Colon; Colonic Neoplasms; Colonoscopy; Deoxycholic Acid; Female; Humans; Intestinal Mucosa; Male; Mitotic Index

Bile acids are important in the etiology of colorectal cancer. Bile acids induce apoptosis in colonic goblet cells at concentrations comparable to those found in fecal water after high-fat meals. Preliminary evidence indicated that cells of the normal-appearing (nontumorous) portion of the colon epithelium of colon cancer patients are more resistant to bile salt-induced apoptosis than are cells from normal individuals. In the present study, 68 patients were examined, and biopsies were taken at 20 cm from the anal verge, cecum, and descending colon. The patients included 17 individuals with a history of colorectal cancer, 37 individuals with adenomas, and 14 individuals who were neoplasia free. The mean bile salt-induced apoptotic index among normal individuals was 57.6 +/- 3.47 (SE), which differed significantly (P < 0.05) from the mean value of 36.41 +/- 3.12 in individuals with a history of colon cancer. The correlation between independent observers was 0.89 (P < 0.001), indicating good interobserver reliability. Components of variance comparing interindividual versus intraindividual sources of variation suggested that site-to-site variability, both between regions of the colon and for adjacent biopsies, was larger than the interpatient variability for individuals with a history of neoplasia. Therefore, there was "patchiness" of the susceptibility of regions of the colon to bile acid-induced apoptosis in individuals with a history of neoplasia (a patchy field effect). There was no obvious correlation of low-apoptotic index regions with regions in which previous neoplasias had been found and removed. On the other hand, for normal, i.e., neoplasia-free, individuals, there was relatively less intraindividual variation compared to interindividual variation. Our assay shows an association between resistance to bile acid-induced apoptosis, measured at 20 cm from the anal verge, and colon cancer risk. Thus, this assay may prove useful as a biomarker of colon cancer risk.

Topics: Adenoma; Anal Canal; Apoptosis; Bile Acids and Salts; Biological Assay; Colon, Sigmoid; Colonic Neoplasms; Colonic Polyps; Colorectal Neoplasms; Deoxycholic Acid; Dietary Fats; Disease Susceptibility; Drug Resistance; Feces; Humans; Intestinal Mucosa; Observer Variation; Quality Control; Rectum; Risk

The high incidence of colorectal cancer in Western society is believed to be strongly related to diet. Mutation of the p53 gene is a late event in colorectal carcinogenesis, and thus, the majority of pre-malignant adenomas express wild-type p53. As loss of p53 protein function is an important step in colorectal carcinogenesis, we investigated whether naturally occurring lumenal factors can modulate the expression of p53 in non-tumorigenic human colonic adenoma cell lines. Levels of p53 protein and mRNA were measured in adherent cells which had been incubated with growth-inhibitory concentrations of sodium butyrate (a by-product of dietary fibre fermentation) or sodium deoxycholate (a bile acid) for up to 48 hr. We report that both butyrate and deoxycholate can down-regulate the expression of wild-type and mutant p53. In contrast, incubation for 48 hr with the endogenous inhibitory growth factor TGFbeta1 did not alter p53 protein expression. Thus, in addition to cellular mechanisms which regulate p53 function, such as post-translational stabilisation, nuclear exclusion, negative feedback inhibition of p53 mRNA translation or binding of p53 by cellular proteins, p53 protein levels also may be regulated by changes in the level of p53 gene transcription. Furthermore, we show that lumenal factors are able to affect directly the expression of p53 protein in colonic epithelial cells.

Topics: Adenoma; Butyrates; Butyric Acid; Cell Division; Cholagogues and Choleretics; Colonic Neoplasms; Deoxycholic Acid; Down-Regulation; Gene Expression Regulation, Neoplastic; Histamine Antagonists; Humans; RNA, Messenger; Transforming Growth Factor beta; Tumor Cells, Cultured; Tumor Suppressor Protein p53

Experimental dietary studies of human colorectal carcinogenesis are usually based on the AIN-76A diet, which is dissimilar to human food in source, preparation, and content. The aims of this study were to examine the feasibility of preparing and feeding rats the diet of a specific human population at risk for colorectal neoplasia and to determine whether changes in the colonic morphology and metabolic contents would differ from those resulting from a standard rat diet. The mean daily food intake composition of a previously evaluated adenoma patient case-control study was used for the "human adenoma" (HA) experimental diet. Foods were prepared as for usual human consumption and processed by dehydration to the physical characteristics of an animal diet. Sixty-four female Sprague-Dawley rats were randomized and fed ad libitum the HA or the AIN-76A diet. Every eight weeks, eight rats from each group were sacrificed, and the colons and contents were examined. Analysis of the prepared food showed no significant deleterious changes; food intake and weight gain were similar in both groups. Compared with the controls, the colonic contents of rats fed the HA diet contained significantly less calcium, concentrations of neutral sterols, total lipids, and cholic and deoxycholic acids were increased, and there were no colonic histological changes other than significant epithelial hyperproliferation. This initial study demonstrated that the HA diet can be successfully processed for feeding to experimental animals and is acceptable and adequate for growth but induces significant metabolic and hyperproliferative changes in the rat colon. This dietary model may be useful for studies of human food, narrowing the gap between animal experimentation and human nutritional research.

Topics: Adenoma; Animals; Bile Acids and Salts; Calcium; Colon; Colorectal Neoplasms; Deoxycholic Acid; Diet; Disease Models, Animal; Epithelium; Fatty Acids; Female; Rats; Rats, Sprague-Dawley; Weight Gain

The short chain fatty acids acetate, propionate and butyrate are produced when dietary fibre is fermented by the colonic bacteria. We have previously shown that sodium butyrate induces apoptosis in 3 colorectal tumour cell lines. We have extended our study to 3 adenoma and 4 carcinoma cell lines and investigated whether propionate and acetate also induce apoptosis. All 3 short chain fatty acids induced apoptosis at physiological concentrations, but of the 3, butyrate was the most effective. Since these fatty acids are produced as a result of bacterial fermentation of dietary fibre, this may in part explain the correlation between a high-fibre diet and low colorectal cancer incidence. Sodium butyrate induced apoptosis in all 7 of the cell lines studied; however, 2 of the 4 carcinoma cell lines (PC/JW/FI and S/KS/FI) were more resistant to butyrate-induced apoptosis than the 3 adenoma cell lines, suggesting that at least some carcinomas may evolve mechanisms to protect the cells from the induction of apoptosis. The bile acid deoxycholic acid has previously been reported as a possible tumour promoter in the large intestine and its levels are reduced by dietary fibre. Concentrations of between 10 nM and 0.1 mM had no effect on either the proliferation or apoptosis of colonic tumour cells in vitro. However, a significant induction of apoptosis was obtained at a concentration of 0.5 mM. These results may have significance for the aetiology of colorectal cancer.

Topics: Acetates; Adenoma; Apoptosis; Butyrates; Carcinoma; Colorectal Neoplasms; Deoxycholic Acid; DNA Damage; DNA, Neoplasm; Fatty Acids, Volatile; Humans; In Vitro Techniques; Propionates; Tumor Cells, Cultured

A positive association between deoxcholic acid (DCA) in the serum and colorectal adenomas, the precursors of colorectal cancer has recently been found, which supported the hypothesis of a pathogenic role of DCA in colonic carcinogenesis. This approach was based on the hypothesis that DCA formed in the colon is absorbed into the portal venous blood and exhibits a constant spillover to the systemic circulation. To further substantiate this hypothesis this study investigated whether in the serum of adenoma patients DCA was higher in the unconjugated fraction, which originates directly from the colon. DCA was found to be 2.8-fold higher in the unconjugated fraction of patients with colorectal adenomas than in controls (0.89 v 0.32 mumol/l, p < 0.0025), 1.9-fold in the total DCA fraction (1.89 v 0.95 mumol/l, p < 0.0001), and 1.4-fold in the conjugated fraction (0.67 v 0.47 mumol/l, p < 0.05). It was further found that the bacterial isomerisation product 3 beta-DCA was twofold higher in the unconjugated fraction of adenoma patients than in controls (0.08 v 0.04 mumol/l, p = 0.27), 1.8-fold in the total iso-DCA fraction (0.11 v 0.06 mumol/l, p < 0.05), and 1.5-fold in the conjugated iso-DCA fraction (0.03 v 0.02 mumol/l, p = 0.68). The data suggest that the positive association between the serum DCA concentration and colorectal adenoma as described previously results from the DCA fraction that is absorbed from the colon. This further supports a pathogenic role of DCA in the carcinogenesis of colorectal cancer.

Topics: Adenoma; Bile Acids and Salts; Cocarcinogenesis; Colorectal Neoplasms; Deoxycholic Acid; Humans; Male; Middle Aged

Bile acids are believed to play a role in the etiology of colorectal cancer. To investigate a possible relationship between bile acids and colorectal tumors, duodenal bile acids were analyzed in 18 patients with colorectal adenomas, 18 patients with colorectal carcinoma and 18 control subjects. Using high performance liquid chromatography and immobilized 3 alpha-hydroxysteroid dehydrogenase in column form, significant increases in the proportion of chenodeoxycholic acid and significant decreases in the proportion of deoxycholic acid and lithocholic acid were found in the bile of patients with colorectal adenoma or carcinoma compared with the control subjects. The data support the concept that bile acids have a role to play in the development of large bowel tumors.

Topics: Adenoma; Aged; Bile Acids and Salts; Carcinoma; Chenodeoxycholic Acid; Colorectal Neoplasms; Deoxycholic Acid; Duodenum; Female; Humans; Intestinal Secretions; Lithocholic Acid; Male; Middle Aged

Topics: Adenoma; Colorectal Neoplasms; Deoxycholic Acid; Humans

Epidemiological and animal studies have suggested that the secondary bile acid deoxycholic acid is cocarcinogenic in colorectal cancer, but this hypothesis was not confirmed by case-control studies investigating fecal bile acids.. Individual serum bile acid concentrations were investigated in 25 men and 25 women with colorectal adenomas and in an equal number of age- and sex-matched controls by gas-liquid chromatography.. Deoxycholic acid levels were significantly higher in the sera of men with colorectal adenomas (1.70 +/- 0.59 vs. 1.16 +/- 0.39 mumol/L, P < 0.0005) and in a combined analysis of both sexes (1.47 +/- 0.78 vs. 1.08 +/- 0.39 mumol/L, P < 0.0025). Six- and 12-month follow-up measurements of deoxycholic acid concentrations in a subgroup of 22 men and 17 women showed higher serum levels in men with adenomas, indicating that measurement of deoxycholic acid concentration may be a reliable parameter to investigate its pathogenetic role in colonic neoplasia.. The data of this study support the hypothesis that deoxycholic acid may play a role in the pathogenesis of colorectal cancer.

Topics: Adenoma; Adult; Aged; Bile Acids and Salts; Colorectal Neoplasms; Deoxycholic Acid; Female; Follow-Up Studies; Humans; Male; Middle Aged; Osmolar Concentration; Reference Values; Sex Characteristics

Peroral sulpholithocholic acid (SLC) promoted colonic tumorigenesis in conventional rats. We then tested this compound in the mouse, a species with different bile acid metabolism from the rat. Female conventional ICR mice received 0.5 mg of N-methyl-N-nitrosourea (MNU) three times in one week intrarectally or 16 mg/kg body weight of 1,2-dimethylhydrazine (DMH) subcutaneously once a week for 10 weeks, followed by a basal diet (CE-2), or CE-2 containing SLC or lithocholic acid (LC) (both at 0.5 mmol/100 g CE-2) for 40 weeks. At autopsy, numbers of mice bearing colonic neoplasms were 4/26 (15%) in the MNU + CE-2, 4/23 (17%) in the MNU + SLC, 5/28 (18%) in the MNU + LC, 12/24 (50%) in the DMH + CE-2, 6/23 (26%) in the DMH + SLC and 11/27 (41%) in the DMH + LC group. The DMH + SLC group had less adenocarcinomas than did the DMH + CE-2 and the DMH + LC group (P < 0.05). Total faecal bile acids in the mice fed on bile salts showed threefold increases compared with those on the basal diet. Sulphates constituted an average 7% and 19% of faecal bile acids in the MNU + SLC and DMH + SLC group, respectively. These results indicated that effects of peroral SLC on colonic carcinogenesis correlated with the degree of desulphation of SLC in the intestine and sulphates per se inhibited colonic carcinogenesis.

Topics: 1,2-Dimethylhydrazine; Adenocarcinoma; Adenoma; Administration, Oral; Administration, Rectal; Animals; Bile Acids and Salts; Carcinogens; Carcinoma, Squamous Cell; Cholic Acids; Colon; Colonic Neoplasms; Deoxycholic Acid; Dimethylhydrazines; Feces; Female; Germ-Free Life; Injections, Subcutaneous; Lithocholic Acid; Methylnitrosourea; Mice; Mice, Inbred ICR

In this necroscopy study the relation between carriage and size of colorectal polyps was correlated with luminal steroid concentrations in respect to malignant risk. Of the 92 subjects entered into the study, 68 had adenomatous polyps of the large bowel, of which 19 had adenomas > 0.9 cm in diameter (large adenomas), 26 in the range 0.5-0.9 cm in diameter (medium adenomas) and 23 of 0.4 cm or less in diameter (small adenomas). Sixty-three percent of subjects carrying large adenomas and 26% of persons carrying small adenomas had an abnormal ratio (> 1.0) of lithocholic acid to deoxycholic acid in intestinal contents as compared to 17% of the adenoma-free comparison group (n = 24). These findings support the suggestion that the ratio of lithocholic acid to deoxycholic acid as a faecal marker may be a useful adjunct to screening procedures for colorectal cancer.

Topics: Adenoma; Aged; Bile Acids and Salts; Biomarkers, Tumor; Cholestanol; Cholesterol; Cholesterol Esters; Colonic Polyps; Deoxycholic Acid; Feces; Female; Gastrointestinal Contents; Humans; Lithocholic Acid; Male; Middle Aged; Phytosterols; Polyps; Rectal Neoplasms; Steroids; Sterols

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Bile Acids and Salts; Cell Cycle; Cell Division; Chenodeoxycholic Acid; Cholesterol; Cholic Acid; Cholic Acids; Colon; Colonic Neoplasms; Colonic Polyps; Deoxycholic Acid; Feces; Female; Humans; Lithocholic Acid; Male; Middle Aged; Phytosterols; Rectum; Sterols

Patients with familial adenomatous polyposis have an excess risk for adenomas and cancers of the upper and lower gastrointestinal tract. In the upper intestine these lesions occur mainly around the ampulla of Vater and they parallel mucosal exposure to bile. In view of this finding and of evidence that bile acids play a role in colorectal carcinogenesis, biliary bile acid profiles were determined in 29 patients with familial adenomatous polyposis (12 before colectomy, 17 after colectomy) and in 28 patients without familial adenomatous polyposis (all with colons in situ). Patients with familial adenomatous polyposis had a higher total biliary bile acid concentration than the others. The bile of patients with polyposis had a greater proportion of chenodeoxycholic acid and a lower proportion of deoxycholic acid than did the bile of patients without polyposis. The ratio of chenodeoxycholic acid and its metabolite lithocholic acid to cholic acid and its metabolite deoxycholic acid, which is related to subsequent bile acid profiles in the colon, was higher in patients with polyposis. Because bile acids influence cellular proliferation, these findings may be of importance with respect to intestinal adenoma and cancer growth.

Topics: Adenoma; Adenomatous Polyposis Coli; Adult; Bile Acids and Salts; Biliary Tract; Chenodeoxycholic Acid; Colon; Deoxycholic Acid; Duodenal Neoplasms; Duodenum; Female; Gallbladder; Humans; Male

We have developed an isotope dilution method for determination of deoxycholic acid pool size and input rate which employs oral administration of 50 mg of [24-13C]deoxycholic acid and serum sampling. The method has been validated by classical isotope dilution technique using [24-14C]deoxycholic acid and bile sampling in five patients with colonic adenomas. Excellent agreement between pool sizes and input rates determined with 13C/12C isotope ratio measurements in serum and 14C measurements in bile was obtained when isotope ratios were measured in the conjugated fraction of deoxycholic acid in serum. We conclude that pool size and input rate of deoxycholic acid can accurately be determined by blood sampling after oral administration of [24-13C]deoxycholic acid, therewith eliminating the use of radioactive tracers and the need for bile sampling.

Topics: Adenoma; Adult; Aged; Carbon Isotopes; Carbon Radioisotopes; Colonic Neoplasms; Deoxycholic Acid; Humans; Isotope Labeling; Kinetics; Middle Aged

A promoting effect of large bowel contents on colonic carcinogenesis as seen in the animal model is still incompletely explored in man. We investigated simultaneously deoxycholate absorption (as marker of colonic mucosal exposure to tumour promoting bile salt metabolites), mouth-anus transit time, and the ratio of anaerobic to aerobic bacteria in stool in 10 persons with colonic adenomas and in 10 age matched control subjects. We found that anaerobic/aerobic ratios and colonic deoxycholate absorption were higher in patients with colonic adenomas (p less than 0.002 and p less than 0.001) and that these parameters were clearly interrelated, which also applied to intestinal transit times and the anaerobic/aerobic ratios. These data are consistent with a promoting effect of the intracolonic environment on development of adenomas in man. Long term induction of a more aerobic colon flora and shortening of intestinal transit time may diminish bile-salt induced tumour promotion in adenoma patients.

Topics: Adenoma; Bacteria; Colon; Colonic Neoplasms; Deoxycholic Acid; Feces; Female; Humans; Intestinal Absorption; Male; Middle Aged; Risk; Time Factors