Bile acid mechanism

Various mechanisms have been proposed to explain the hypocholesterolemic effect of GA (Annison et al., 1995 Tiss et al., 2001). Some studies have suggested that the viscosity of fermentable dietary fiber contributes substantially to the reduction of lipids in animals and humans (Gallaher et al., 1993 Moundras et al., 1994). However, other studies suggested that this property is not related to plasma lipids (Evans et al., 1992). The mechanism involved is clearly linked to increased bile acid excretion and fecal neutral sterol or a modification of digestion and absorption of lipids (Moundras et al., 1994). 

Bai CL, Stacey NH. 1993. Mechanism of trichloroethylene-induced elevation of individual serum bile acids. II. In vitro and in vivo interference by trichloroethylene with bile acid transport in isolated rat hepatocytes. Toxicol Appl Pharmacol 121 296-302. 

The consequence of bacterial bile acid metabolism [66, 74,77] is hardly clinically significant malabsorption [6] in otherwise healthy individuals [32,79], but in predisposed individuals this may be different. Accordingly, omeprazole interferes with the absorption of vitamin B12 [80-83] and protein assimilation [84], The mechanism for altered vitamin B12 absorption is prevention of its cleavage from dietary protein [83], for which the importance of the concurrent bacterial overgrowth has not yet been ruled out. 

The answer is c. (Hardman, pp 887, 889.) Bile acid-binding resins bind more than just bile acids, and binding of simvastatin to cholestyramine is the most likely mechanism for decreased Gl absorption. Cholestyramine may also bind to several other drugs, including digoxin, benzothiadiazides (thiazides), warfarin, vancomycin, thyroxine (T4), and aspirin. Medications should be given one hour before or four hours after cholestyramine. 

Bile acids and salts have been found to enhance the absorption of both calcium and vitamin D hence, to increase calcium absorption both directly and indirectly (3,37). However, the ability of some dietary fibers such as lignin and pectin to absorb conjugated and deconjugated bile salts onto their surfaces to be excreted in the feces (a mechanism credited to the hypocholesterolemic effect of some dietary fibers) may result in an overall decrease in calcium absorption from the gastrointestinal tract (7,33,38-40). 

The mechanisms by which various forms of dietary fiber influence calcium bioavailability apparently also differ. In some cases, apparent dietary fiber effects on calcium bioavailability may be secondary to effects on bile acid and salt secretion and reabsorption or to other dietary components. 

In addition to more rapid absorption of lipids in animals fed casein, another mechanism that may be operative is decreased clearance of circulating lipids. Rabbits fed a casein-based semipurified diet excreted significantly less cholesterol but more bile acids in their feces than animals fed a commercial diet (18). The total sterol excretion in feces of the animals fed the casein diet was half that of the rabbits fed the stock diet. Huff and Carroll (19) found that rabbits fed soy protein had a much faster turnover rate of cholesterol and a significantly reduced rapidly exchangeable cholesterol pool compared with rabbits fed casein. Similar studies performed in our laboratory revealed that the mean transit time for cholesterol was 18.4 days in rabbits fed soy protein, 36.8 days in rabbits fed casein, 33.7 days in rabbits fed soy plus lysine, and 36.3 days in rabbits fed casein plus arginine. These data suggest that addition of lysine to soy protein... 

Bjorkemd, I., 1992, Mechanism of degradation ofthe steroid side chain in the formation of bile acids, 7. Lipid Res. 33 455-471. 

D. Stamp, Antibiotic therapy may induce cancers in the colon and breasts through a mechanism involving bile acids and colonic bacteria. Medical Hypotheses, 2004, 63, 555-556. 

Glutathione S transferases bind bile acids in vitro but doubt has been cast over whether this happens in vivo as these enzymes were not labelled by fluorescently labelled bile acids in experiments to identify the carrier proteins but may play a role with the raised levels in cholestasis. Liver fatty-acid-binding protein has been shown to bind bile acids by using a displacement assay with fluorescent fatty-acid ligand. This work clearly showed displacement to be directly related to hydrophobicity, such that lithocholate conjugates had the greatest effect. This may indicate a mechanism to minimise toxicity within the hepatocyte. 

These deconjugated secondary bile acids are lipophilic and are believed to passively diffuse across the colon and enter the blood supply for return to the liver. Little is known of the mechanism, although in ASBT knockout mice there is an increase in OSTa/OSTp mRNA within the proximal colon.This could simply reflect reduced bile-acid uptake in the terminal ileum and a response to increased bile-acid levels entering the colon. 

Other studies (Table 3.2) indicate that exposure to high physiological concentrations of bile acids, if repeated over a long period, increases the risk of GI cancer. A reasonable hypothesis is that bile acids act by a common underlying mechanism at various sites within the GI tract. Nevertheless, conditions vary widely from site to site within the GI tract, and it is certainly possible that at any particular site some factor(s) other than bile-acid exposure, or in combination with bile-acid exposure, is more important in carcinogenesis at that site. 

L. A. Booth and R. F. Bilton, Genotoxic potential of the secondary bile acids a role for reactive oxygen species, in DNA and Free Radicals Techniques, Mechanisms Applications, O.I. Arouma and B. Halliwell, Editor, 1998, OICA International London, 161. 

Given that bile acids, particularly deoxycholic acid, can damage DNA, one might expect bile acids to demonstrate mutagenic effects. This might be particularly apparent in eukaryotic cells that could sustain mitochondrial damage or release NO via the mechanisms described above. 

Mechanisms of the Carcinogenic Activity of Secondary Bile Acids... 

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