Glycocholic acid, bile salt

See also Bile Acids, Bile Salts, Glycine, Taurine, Glycocholate, Taurocholate, Chenodeoxycholate, Bile Salts and Emulsion of Fats... 

Mammalian bile contains sodium salts of conjugated bile acids, e.g. glycocholic acid and taurocholic acid, in which cholic acid is combined (amide linkage) with glycine and taurine respectively. 

Bile acids, which exist mainly as bile salts, are polar carboxylic acid derivatives of cholesterol that are important in the digestion of food, especially the solubilization of ingested fats. The Na and salts of glycocholic acid and tauro-cholic acid are the principal bile salts (Ligure 25.41). Glycocholate and tauro-cholate are conjugates of cholic acid with glycine and taurine, respectively. 

FIGURE 25.41 Cholic acid, a bile salt, is synthesized from cholesterol via 7o -hydroxy-cholesterol. Conjugation with taurine or glycine produces taurocholic acid and glycocholic acid, respectively. Taurocholate and glycocholate are freely water-soluble and are highly effective detergents. 

Recently, molecular biology studies have been carried out on hepatic uptake transporters. With regard to the Na+-dependent hepatic uptake of bile acids, Na+-taurocholate cotransporting polypeptide (Ntcp/NTCP) has been cloned from both rodents and humans [14-17]. Ntcp/NTCP accepts bile salts, such as taurocholate and glycocholate, as well as some anionic compounds such as dehydroepian-drosterone sulfate and bromosulfophthalein [16, 18]. However, the presence of unidentified Na+-dependent transporters for anionic drugs (e.g., bumetanide) has also been suggested [19, 20]. 

Bile salt export pump (BSEP gene symbol ABCB11) mediates the biliary excretion of nonconjugated bile salts, such as taurocholic acid, glycocholic acid and cholic acid, and therefore is responsible for the formation of the bile acid-dependent bile flow [97, 98]. Its hereditary defect results in the acquisition of PFIC2, a potentially lethal disease which requires liver transplantation [17, 81, 82, 99]. As discussed in Section 12.5.2, the inhibition of BSEP following drug administration may result in cholestasis. 

The addition of absorption enhancers, like bile salts (glycocholate), fatty acids (Unoleic acid), surfactants (lecithins, polyoxyethylene-9-lauryl ether or N-lauryl-P-D-maltopyra-noside) and chelators (EDTA) can significantly increase the absorption of various proteins. However, the application of enhancers is limited by their toxicity. For example polyoxyethyl-ene-9-lauryl ether and sodium glycocholate caused serious oedema, haemorrhage and inflammation of the lung after intratracheal instillation [39]. 

The bile acids are usually conjugated to the amino acids, glycine or taurine, as shown for the formation of glycocholate in figure 20.21. It is in this form that the bile acids are secreted via the gallbladder into the intestine where they are critically important for the solubilization of dietary lipids. At pH 7, these acids exist as the sodium salts and are often referred to as bile salts. Of course in the acidic environment of the small intestine, they occur largely in their acidic form. 

Conversion of a cholic acid into glycocholate. Glycocholate is an example of a bile salt. The bile salts solubilize lipids in the small intestine so they can be degraded by lipases. 

A special consideration in the digestion of fats is that they are not water soluble and cannot be placed in aqueous solution along with the water-soluble lipase digestive enzymes. However, intimate contact is obtained by emulsification of fats through the action of bile salts from glycocholic and taurocholic acids produced from cholesterol in the liver ... 

Bile salts (bile acids) are the major excretory form of cholesterol. These polar compounds are formed in the liver by converting cholesterol into the activated intermediate cholyl CoA and then combining this compound with either glycine, to form glycocholate, or taurine, to form taurocholate. The detergentlike bile salts are secreted into the intestine where they aid the digestion and uptake of dietary lipids. 

Bile salts (or bile acids) are polar derivatives of cholesterol and constitute the major pathway for the excretion of cholesterol in mammals. In the liver, cholesterol is converted into the activated intermediate cholyl CoA which then reacts either with the amino group of glycine to form glycocholate (Fig. 3a), or with the amino group of taurine (H2N-CH2-CH2-S03", a derivative of cysteine) to form taurocholate (Fig. 3b). After synthesis in the liver, the bile salts glycocholate and taurocholate are stored and concentrated in the gall bladder, before release into the small intestine. Since they contain both polar and nonpolar... 

The possible reasons for the different behavior of natural surfactants could include the following. Natural surfactants lead to surface tension values higher than those corresponding to the same concentration of a synthetic surfactant. The ability to nullify the aqueous layer resistance could be related with the surface tension values. However, the micelles of bile salts are smaller and more rigid than the micelles of synthetic surfactants. The solubilization potential of bile salts is increased in the presence of lecithins and fatty acids. For instance, the absorption rate constants obtained in the presence of sodium taurocholate and glycocholate mixed-micelles with lecithin for a series of acids were significantly lower than those obtained in the presence of simple micelles of the same bile salts [29, 30]. 

Typical solid lipids used are glycerides and/or fatty acids, and may constitute 30% of the formulation. These are from the same family of lipids found in parenteral nutrition emulsions, such as Intralipid, which have been successfully administered intravenously for several decades. Typical excipients are Dynasan 112, composed of short chain fatty acids, Compritol, lecithin, used as an emulsifier, and surfactants such as polysorbate 80, polaxamer 188, PVP, bile salts such as sodium glycocholate, and Span 85. Water can be replaced with oils or PEG 600 to yield dispersions which can be filled into soft gelatin capsules. 

A. This compound is the bile salt glycocholic acid. During its synthesis, the ring structure of cholesterol is hydroxylated and reduced, and the side chain is oxidized and conjugated with... 

Synthesis of the Bile Acid Cholic Acid (a) and the Bile Salt Glycocholate (b). 

The orientation of the mobile side chain at C-17 has not been unambiguously resolved for alkali salts of bile acids in aqueous solutions. However, evidence adduced from the differences in calculated molecular areas of surface-adsorbed bile salts versus spread monomolecular layers of insoluble bile acids at their collapse pressures [12] suggest that the side chain, when ionized, lies a-axial with respect to the plane of the molecule, but when undissociated lies parallel to the surface. Effects of systematic variations in pH between 1 and 13 on the surface areas of spread and adsorbed glycocholate molecules suggest that the difference between the two surface... 

Glycine is also important for certain detoxifications. For example, benzoic acid, which is found in numerous foods as a preservative, is detoxified by conjugation with glycine in an amide link to produce hippuric acid. The hippuric acid is then rapidly removed via the kidney. This amide bond to an acid group is not unique to benzoic acid. It also occurs in glycocholic acid (a combination of glycine and cholic acid) and taurocholic acid (a combination of taurine and cholic acid), both important bile salts. 

Bile acids are usually conjugated in amide linkage with the amino acid glycine or taurine, giving bile salts. The cholic acid conjugates with glycine and taurine are called glycocholate and taurocholate, respectively. 

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