The effect of two hydrophilic
bile acids,
murideoxycholic acid (3 alpha,6 beta-dihydroxy-5 beta-
cholanoic acid) and
ursodeoxycholic acid, on
cholesterol and
bile acid metabolism and hepatic pathology and
gallstone composition was studied in the prairie dog.
Cholesterol gallstones were induced by feeding a diet containing 1.2%
cholesterol for 75 days. The animals were divided into six groups, and
gallstone regression was studied as follows: groups 2 and 5, chow plus 0.2%
cholesterol; groups 3 and 6, chow plus 0.2%
cholesterol plus 0.15%
ursodeoxycholic acid; groups 4 and 7, chow plus 0.2%
cholesterol plus 0.15%
murideoxycholic acid. Animals in groups 2 to 4 were killed after an additional 6 wk; animals in groups 5 to 7 were killed after an additional 12 wk.
Gallstone dissolution did not occur in any group. The
gallstones in groups 2, 3, 5 and 6 were typical
cholesterol aggregates, as determined by polarized light microscopy and Fourier transform infrared spectrometry. The
gallstones of the
murideoxycholic acid group were large, solitary, dark stones that appeared radiopaque under 22 kVp x-ray examination. Scanning electron microscopy showed that in these stones the
cholesterol crystals had been replaced by an amorphous material, both within the stone and on the stone surface. Chemical analysis indicated that at the end of 12 wk the
calcium/
sodium salt of the
taurine conjugate of
murideoxycholic acid (murideoxycholyl
taurine) comprised 70% of the stones;
protein,
cholesterol and small amounts of other
bile salts were also present. In vitro studies confirmed the insolubility of the
sodium and
calcium salts of murideoxycholyl
taurine. These studies indicate that the hydrophilic
bile acids,
murideoxycholic acid and
ursodeoxycholic acid, did not achieve
gallstone dissolution under the conditions used. In the animals fed
murideoxycholic acid, an insoluble
calcium salt of murideoxycholyl
taurine replaced
cholesterol as the major constituent of gallbladder stones. This is the first example of an insoluble dihydroxy
taurine-conjugated
bile acid; administration of the unconjugated
bile acid induced precipitation of a kind of
gallstone not previously reported. The final result was transformation of
cholesterol stones to
bile salt stones.