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Journal of Lipid Research, Vol 33, 617-626, Copyright © 1992 by Lipid Research, Inc.
AF Hofmann and KJ Mysels
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)
REVIEWS
Bile acid solubility and precipitation in vitro and in vivo: the role of conjugation, pH, and Ca2+ ions
Department of Medicine, University of California, San Diego, La Jolla 92093.
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