Solubility of bile acids

On the basis of surface and bulk interaction with water. Small [85] classified bile acids as insoluble amphiphiles and bile salts as soluble amphiphiles. On account of the undissociated carboxylic acid group, the aqueous solubility of bile acids is limited [35] in contrast, many bile salts have high aqueous solubilities as monomers [33] and, in addition, their aqueous solubilities are greatly enhanced by the formation of micelles [5,6]. Because many bile salts are weak electrolytes, their ionization and solubility properties are more complicated than those of simple inorganic or organic electrolytes [5,35]. For example, the p/Tj, values of bile acids in water vary markedly as functions of bile salt concentration and, because micelles formed by the A (anionic) species can solubilize the HA (acid) species [5,35], the equilibrium precipitation pH values of bile acids also vary as functions of bile salt concentration. Finally, certain bile salts are characterized by insolubility at ambient temperatures [2,5,6,86,87], only becoming soluble as micelles at elevated temperatures (the critical micellar temperature) [6]. 

From the start of precipitation (X) onward, there are two phases present (liquid plus crystal), and since solutions between Y and X are unstable, the only portion of the curve that is in thermodynamic equilibrium for the single liquid phase is portion WY. Point 7, therefore, represents the maximum solubility of bile acid (HA) in the bile salt solution (A ) before supersaturation occurs. 

NORMAND F L, ORY R L, MOD R R (1987) Binding of bile acids and trace minerals by soluble hemicelluloses of rice The ability of rice fiber components to bind bile acids may play a role in lowering serum cholesterol. Food Technology, 41(2) 86-90. 

Bile acids secreted into the small intestine facilitate absorption of fat-soluble vitamins and cholesterol. The majority of bile acids are reabsorbed from the intes-... 

Fig. 21.7. Solubility of a very poorly soluble drug, candersartan cilexitil, at different concentrations of bile acid/lecithin (2.5 1).

Figure 1.1 illustrates a condensed version of the classical pathway of bile-acid synthesis, a series of 12 enzymatic reactions that convert cholesterol, which is insoluble, into BAs, which are water soluble. The cholesterol is first converted to 7 alpha-hydroxy cholesterol, followed by the series of enzymatic transformations, eventually producing cholic and chenodeoxycholic acids (not all steps shown). The rate-limiting enzyme in this pathway is cholesterol 7 alpha-hydroxylase (CYP 7A1), which originates from microsomal cytochrome P-450 enzymes, expressed only in the liver hepatocytes. 

Vesicular transport of bile acids has not been demonstrated under normal conditions, shown by using isolated rat hepatocyte couplets and fluorescently labelled bile acids. In these experiments confocal microscopy found no evidence of sequestering into clusters and colchicine disruption of microtubular function did not affect bile-acid transport. This makes it unlikely that vesicle transport plays a role and it is now believed that bile acids traverse the hepatocyte by diffusion through the cytosol while bound to soluble proteins. It is worth considering the caveat that fluorescently labelled bile acids, while very useful tools, do differ structurally from endogenous bile acids with increased hydro-phobicity leading to greater retention by cells. ... 

The cholesterol excreted with the bile is poorly water-soluble. Together with phospholipids and bile acids, it forms micelles (see p. 270), which keep it in solution. If the proportions of phospholipids, bile acids and cholesterol shift, gallstones can arise. These mainly consist of precipitated cholesterol (cholesterol stones), but can also contain Ca " salts of bile acids and bile pigments (pigment stones). 

Itching associated with retention of bile acids is ameliorated by treatment with the bile acid binding resin cholestyramine. Fat soluble vitamin (A, D and K) deficiency may require administration of supplements. Direct toxic effects of alcohol associated with dietary deficiency may require soluble B vitamin administration. 

Gastrointestinal enzyme activities tend to be lower in the newborn than in the adult. Activities of -amylase and other pancreatic enzymes in the duodenum are low in infants up to 4 months of age. Neonates also have low concentrations of bile acids and lipase, which may decrease the absorption of lipid-soluble drugs. 

The solubility of cholesterol in bile is determined by the relative proportions of bile acids, lecithin, and cholesterol. Although prolonged ursodiol therapy expands the bile acid pool, this does not appear to be the principal mechanism of action for dissolution of gallstones. Ursodiol decreases the cholesterol content of bile by reducing hepatic cholesterol secretion. Ursodiol also appears to stabilize hepatocyte canalicular membranes, possibly through a reduction in the concentration of other endogenous bile acids or through inhibition of immune-mediated hepatocyte destruction. 

Effect of Bulk pH on Behavior and Solubility of Oleic Acid in Bile Salt Solution. Figure 2 shows the effect of bulk pH on the behavior and solubility of oleic acid in 0.15M buffer (above) and in 4 mM sodium glycodeoxycholate (below). In buffer, oleic acid has an extremely low solubility, and the excess, below pH 6.8, is present as an emulsion. In micellar bile salt solution, the oleic acid is solubilized to some extent. Above pH 6.5, its solubility rises markedly, and the excess now forms a dispersed phase which probably consists of droplets of fatty acid emul-... 

Another possible mechanism involves the effect of saponins on micelle formation. Saponins are known to alter the size or shape of micelles (Oakenfull, 1986 Oakenfull and Sidhu, 1983), an observation that is consistent with decreased bile acid absorption (Stark and Madar, 1993) and increased fecal bile acid excretion (Malinow et al., 1981 Nakamura et al.,1999). Saponins may also directly bind bile acids (Oakenfull and Sidhu, 1989), which would presumably interfere with micelle formation and decrease cholesterol absorption. Other studies have found that saponins decrease the absorption of fat-soluble vitamins (Jenkins and Atwal, 1994) and triglycerides (Han et al., 2002 Okuda and Han, 2001), indicating decreased micelle formation. However, direct evidence showing impaired micelle formation in vivo is lacking. Moreover, Harwood et al. (1993) reported no change in bile acid absorption or interruption of the enterohepatic circulation of bile acids in hamsters fed tiqueside, despite significant reductions in cholesterol absorption. 

It is well known that bile acids are produced in the liver of vertebrates for digestion and absorption of fats and fat-soluble vitamins. Starting from isoprene, a series of biochemical reactions yield a key compound, cholesterol, which is converted to primary bile acids, such as cholic acid (CA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA) and lithocholic acid (LCA). Hereafter the abbreviations of bile acid derivatives can be seen by consulting Table 1 and Figure 1. 

Inclusion crystals of bile acid derivatives can be obtained by direct recrystallization of host and liquid guests. When the guests do not have enough solubility for a host, the third component or the solvent were used. In the case of solid guests, solvents were used as well. The solvent should not form inclusion compounds with the host, and should not interact with host and guest compounds. 

Bile-acid metabolism explains the ability of certain kinds of dietary fiber to help lower serum cholesterol. A molecule of bile acid circulates through the liver and intestine five or more times before finally being eliminated. Soluble fiber (such as that found in oat bran) binds bile acids, but itself cannot be absorbed. Therefore, fiber-bound bile acids are eliminated in the stool. Because bile acids derive from cholesterol, synthesizing more bile acid drains the body s stores of cholesterol, which leads to a reduction in serum cholesterol, and therefore, to a lower risk of coronary artery disease. Eating oat fiber cannot overcome an excessive dietary cholesterol consumption, of course. In other words, consuming excessive amounts of well-marbled steak and expecting to overcome the effects by eating a bran muffin would be foolish. 

In liver cirrhosis, there are several changes reduction in LCAT (with cholesterol ester fall ), HDL and LDL as well as in VLDL, with a corresponding change in their distribution pattern occurrence of hypertriglycerid-aemia and atypical lipoproteins reduction in phospholipid synthesis (28), possibly with greatly impaired structure and function of the biomembranes. Hepatic extraction of bile acids is reduced with the result that they reach the peripheral circulation - even in the early stages of cirrhosis - and give rise to increased serum values. Bile acids have cholestatic and cytotoxic effects. When bile acid metabolism is markedly compromised, enteral absorption of fat-soluble vitamins is impeded, so that A, D, E and K hypovitaminoses may be observed. 

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