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PubMedDate not supplied

Micellar aggregation and membrane partitioning of bile salts, fatty acids, sodium dodecyl sulfate, and sugar-conjugated fatty acids: correlation with hemolytic potency and implications for drug delivery.

The co-administration of a drug with a penetration enhancer (PE) is one method by which the membrane permeability of a drug can be improved. To facilitate PE design, it is important that the molecular basis of PE toxicity and efficacy be examined, so we investigated the membrane affinity and micellar aggregation of a series of synthetic liposaccharide PEs and correlated these properties with hemolytic potency. The influence of liposaccharide alkyl chain length (nc) on the system was studied, and comparisons were made with conventional PEs such as bile salts, fatty acids, and surfactants. The liposaccharides were each synthesized in eight steps in good overall yield. Their critical micelle concentrations (CMCs) in phosphate-buffered saline ranged from 0.207 to 20.2 mM, and it was found that increasing nc by 2 afforded a 1 order of magnitude decrease in the CMC. Immobilized artificial membrane (IAM) chromatography was used to determine each PE's affinity for biological membranes, and an increase in nc caused a significant increase in the extent of membrane binding. A study of hemolytic activity revealed that liposaccharides with an nc of < or = 12 are the most likely to be biocompatible. The CMC values for all PEs showed a negative correlation with hemolytic potency; however, it was PE monomers, not micelles, that were responsible for the onset of hemolysis. The affinity of all enhancers for the IAM displayed a positive correlation with hemolytic potency, and therefore, IAM chromatography can be used to predict PE hemolytic activity. It was concluded that the biocompatibility of liposaccharides can be modulated by minor alterations in nc.

Bile Acids and Salts↗
PubMed1988

Rat intestinal apolipoprotein B gene expression. Evidence for integrated regulation by bile salt, fatty acid, and phospholipid flux.

We previously reported that intestinal apo B48 synthesis in the rat was unaltered by dietary triglyceride intake but demonstrated regulation in response to biliary lipid availability. Studies are now presented in which the mechanisms underlying biliary lipid dependent expression of intestinal apo B48 synthesis have been investigated further. Bile salt replacement was effective in a dose- and structure-dependent manner in reexpressing intestinal apo B48 synthesis after prolonged bile diversion. Further experiments suggested that this effect of bile salt may be related to facilitated uptake of fatty acid. A role for mucosal phospholipid flux was suggested by studies in which infusion of lysolecithin, with or without Na taurocholate, produced complete reexpression of apo B48 synthesis in jejunal enterocytes. Over a four- to sixfold range of apo B48 synthesis rates in both jejunum and ileum, there was no change in apo B mRNA size or abundance as determined by RNA blot hybridization. Analysis of both intestinal mucosa and microsome lipid content in a variety of settings revealed that apo B48 synthesis rates were correlated with microsome triglyceride fatty acid content (r = 0.65, P less than 0.005) but not free fatty acid or phospholipid content. These studies demonstrate a physiologic role for elements of biliary lipid flux in the regulation of apo B gene expression. The data suggest that an integrated mechanism may exist whereby apo B48 synthesis is related to microsome triglyceride flux, particularly at low levels of lumenal substrate availability.

Animals↗
PubMed1992

[The relationship between bile acid and factors relative to gastric cancer].

By high performance liquid chromatography and 3a-hydroxysteroid dehydrogenase determination, we quantitatively analysed the content of 8 combined biliary acid salt and pH of gastric juice from 35 patients with gastric disease and healthy controls. It was found that both the content of various kinds of biliary acid salt and pH value of gastric juice were much higher in patients with gastric cancer, gastric ulcer, and chronic atrophic gastritis than in normal controls, bile acid salt is known to be harmful to gastric mucosa and that the damage becomes more severe with the increase of bile acid salt concentration and prolongation of exposure, therefore our results suggest that the bile acid salt in the gastric juice is one of the carcinogenic factors.

Adult↗
PubMed1981

The effects of cholic acid and bile salt binding agents on 1,2-dimethylhydrazine-induced colon carcinogenesis in the rat.

The theory that bile salts may be colon tumour promoters was tested in the dimethylhydrazine (DMH)-induced rat colon cancer model. Fifty Wistar rats were randomly allocated to one of five experimental group (n = 10), all fed the same standard diet. One group served as saline-injected controls, while the other four groups received DMH (20 mg/kg body weight/rat/week s.c.) for 20 weeks. In addition, each of the DMH-injected groups concurrently received 20 weekly i.g. instillations of one of the following: cholic acid (a bile acid); cholestyramine or aluminium hydroxide (both bile acid binding agents), or water. After a years observation period, all the controls were alive and tumour-free, while all the DMH-injected rats had died of histologically proven colon cancer. Irrespective of the type of gastric instillate, there were no significant differences between the groups in terms of time to tumour presentation, survival, in the necropsy incidence of primary or metastatic colon cancer, or in the numbers of colon tumours per group. The data suggest that bile salts and bile salt binding agents are not colon tumour promoters in the rat. The bile salt theory of colon carcinogenesis may need reappraisal.

1,2-Dimethylhydrazine↗
PubMed2004

Acid and bile salts induce DNA damage in human oesophageal cell lines.

Barrett's oesophagus is an acquired precancerous condition that develops from mucosal injury incurred due to chronic gastro-oesophageal reflux. The aim of this study was to determine if bile and/or acid components of the refluxate can induce DNA damage in vitro. The oesophageal cell lines FLO-1 and HET1-A were exposed to primary bile salts, individually or as a mixture, and the secondary bile salt sodium deoxycholate, in neutral or acidified media. Cells were then examined in the comet assay to measure DNA strand breaks. Cell viability was also monitored. Acidified media induced DNA damage in a pH- and time-dependent manner. The primary bile compounds sodium glycocholate, glycocholic acid, sodium taurocholate and taurochenodeoxycholate, as an equimolar mixture (100 microM), caused a small but significant (P < 0.028) elevation in DNA damage, but only at neutral pH in FLO-1 cells. Sodium deoxycholate (100 microM) caused a significant (P < 0.008) elevation in DNA damage in both cell lines, but again only at neutral pH. These data suggest that specific components of gastro-oesophageal refluxate are capable of causing DNA damage and may participate in the genesis and progression of Barrett's oesophagus via this mechanism.

Barrett Esophagus↗
PubMed2003

Genetic cholestasis, causes and consequences for hepatobiliary transport.

Bile salts take part in an efficient enterohepatic circulation in which most of the secreted bile salts are reclaimed by absorption in the terminal ileum. In the liver, the sodium-dependent taurocholate transporter at the basolateral (sinusoidal) membrane and the bile salt export pump at the canalicular membrane mediate hepatic uptake and hepatobiliary secretion of bile salts. Canalicular secretion is the driving force for the enterohepatic cycling of bile salts and most genetic diseases are caused by defects of canalicular secretion. Impairment of bile flow leads to adaptive changes in the expression of transporter proteins and enzymes of the cytochrome P-450 system involved in the metabolism of cholesterol and bile acids. Bile salts act as ligands for transcription factors. As such, they stimulate or inhibit the transcription of genes encoding transporters and enzymes involved in their own metabolism. Together these changes appear to serve mainly a hepatoprotective function. Progressive familial intrahepatic cholestasis (PFIC) results from mutations in various genes encoding hepatobiliary transport proteins. Mutations in the FIC1 gene cause relapsing or permanent cholestasis. The relapsing type of cholestasis is called benign recurrent intrahepatic cholestasis, the permanent type of cholestasis PFIC type 1. PFIC type 2 results from mutations in the bile salt export pump (BSEP) gene. This is associated with permanent cholestasis since birth. Serum gamma-glutamyltransferase (gamma-GT) activity is low to normal in PFIC types 1 and 2. Bile diversion procedures, causing a decreased bile salt pool, have a beneficial effect in a number of patients with these diseases. However, liver transplantation is often necessary. PFIC type 3 is caused by mutations in the MDR3 gene. MDR3 is a phospholipid translocator in the canalicular membrane. Because of the inability to secrete phospholipids, patients with PFIC type 3 produce bile acid-rich toxic bile that damages the intrahepatic bile ducts. Serum gamma-GT activity is elevated in these patients. Ursodeoxycholic acid therapy is useful for patients with a partial defect. Liver transplantation is a more definitive therapy for these patients.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2003

[Molecular mechanisms regulating transport of low molecular weight substances in the hepatocyte].

Transporters of sinusoidal and lateral membranes mediate uptake of inorganic and organic substances to hepatocyte. In hepatocyte lipophilic compounds are biotransformed (hydroxylated and conjugated) and excreted into bile and urine. Vectorial movement of solutes and water from blood to bile is maintained by pumps of ABC superfamily secreting bile salts (bile acid dependent flow) and other solutes: bilirubin, phospholipids, glutathione and inorganic salts (bile acid independent flow).

Animals↗