Bile acid solubility and precipitation in vitro and in vivo: the role of conjugation, pH, and Ca2+ ions.

Kj Mysels,Af Hofmann

doi:10.1016/s0022-2275(20)41426-9

Kj Mysels, Af Hofmann

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https://doi.org/10.1016/s0022-2275(20)41426-9

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Abstract

The principles governing the in vitro solubility of the common natural conjugated and unconjugated bile acids and salts in relation to pH, micelle formation, and Ca2+ concentration are considered from a theoretical standpoint and then correlated first with experimental observations on model systems and second with the formation of precipitates containing bile acids in health and disease. In vitro, taurine-conjugated bile acids are soluble at strongly acidic pH; glycine-conjugated bile acids are poorly soluble at moderately acidic pH; and many of the common, natural unconjugated bile acids are insoluble at neutral pH. For both glycine-conjugated and unconjugated bile acids, solubility rises exponentially, with increasing pH, until the concentration of the anion reaches the critical micellization concentration (CMC) when micelle formation occurs and solubility becomes practically unlimited. In vivo, in health, conjugated bile acids are present in micellar form in the biliary and intestinal tract. Unconjugated bile acids formed in the large intestine remain at low monomeric concentrations because of the acidic pH of the proximal colon, binding to bacteria, and absorption across the intestinal mucosa. In diseases in which proximal small intestinal content is abnormally acidic, precipitation of glycine-conjugated bile acids (in protonated form) occurs. Increased bacterial formation of unconjugated bile acids occurs with stasis in the biliary tract and small intestine; in the intestine, unconjugated bile acids precipitate in the protonated form. If the precipitates aggregate, an enterolith may be formed. In vitro, the calcium salts of taurine conjugates are highly water soluble, whereas the calcium salts of glycine conjugates and unconjugated bile acids possess limited aqueous solubility that is strongly influenced by bile acid structure. Precipitation occurs extremely slowly from supersaturated solutions of glycine-conjugated bile acids because of metastability, whereas super-saturated solutions of unconjugated bile acids rapidly form precipitates of the calcium salt. In systems containing Ca2+ ions and unconjugated bile acids, pH is important, since it is the key determinant of the anion concentration. For bile acids with relatively soluble calcium salts (or with a low CMC), the concentration of the anion will reach the CMC and micelles will form, thus precluding formation of the insoluble calcium salt. For bile acids, with relatively insoluble calcium salts (or with a high CMC), the effect of increasing pH is to cause the anion to reach the solubility product of the calcium salt before reaching the CMC so that precipitation of the calcium salt occurs instead of micelle formation.(ABSTRACT TRUNCATED AT 400 WORDS)

Highlights

The principles governing the in vitro solubility of the common natural conjugated and unconjugated bile acids and salts in relation to pH, micelle formation, and Ca2' concentration arc considered from a theoretical standpoint and correlated first with experimental observations on model systems and second with the formation of precipitates containing bile acids in health and disease
It is concluded that the pattern of bile acid hydroxylation and conjugation of the common natural primary bile acids has resulted in formation of recycling anionic surfactants that are quite resistant to formation of insoluble calcium salts under the usual physiological conditions where they function as effective solubilizers of biliary and digestive lipids. -Hofmann, A
It is axiomatic that precipitation of a calcium salt will not occur if its solubility product is not reached

Summary

Introduction

The principles governing the in vitro solubility of the common natural conjugated and unconjugated bile acids and salts in relation to pH, micelle formation, and Ca2' concentration arc considered from a theoretical standpoint and correlated first with experimental observations on model systems and second with the formation of precipitates containing bile acids in health and disease. In the presence of Ca2+ions with an activity equal to that present in plasma, bile, or small intestinal content (1-3 mM), the equilibrium concentrations of the bile acid anions in a saturated solution vary over a broad range depending on their structure, on the number, position, and orientation of hydroxy or other substituents, as well as the mode of conjugation (with glycine, with taurine, or unconjugated).

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