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1 Institut für
Pharmazeutische Technologie und Biopharmazie, D-69120 Heidelberg,
Germany; 2 Novartis AG,
The sulfated
bile alcohol scymnol sulfate (ScyS),
3
,7,12,24
,26,27-hexahydroxy-5
-cholestane-26(27)-sulfate,
is the major bile salt in bile of an elasmobranch, the little skate. To
investigate hepatic transport of bile alcohols in skate liver,
[3H]ScyS and a
potential precursor, 3,7,12-trihydroxy-5-cholestane (chtriol), were used as model compounds. Their transport into isolated
hepatocytes was partially saturable, temperature sensitive, and
Na+ independent. The uptake of
ScyS was inhibited by cholyltaurine, and uptake of cholyltaurine was
inhibited by ScyS in a competitive manner. In contrast, uptake of
chtriol was not inhibited by cholyltaurine, suggesting separate
transport systems. ScyS and chtriol showed a choleretic effect in
isolated perfused livers. When ScyS was added to the perfusate of
isolated perfused livers, >25% was found in bile within 7 h. When
chtriol was added to the perfusate, 10% of the dose was secreted into
the bile mainly in the form of polar metabolites, whereas only
nonmetabolized chtriol remained in the livers. The slow bile flow of
40-50 µl/h and the high recovery in the liver suggest that
metabolism may be the rate-limiting step in the hepatic elimination of
chtriol. The major metabolites secreted into bile were identified by
mass spectrometry and chromatography as scymnol and ScyS. To study the
enterohepatic circulation,
[3H]ScyS or
[3H]chtriol was
administered into the duodenum of free-swimming skates, and bile was
collected through exteriorized indwelling cannulas over a 4-day period.
More than 90% of the radioactivity was recovered from bile, indicating
that there was a highly effective absorption in the intestinal
epithelium, as well as specific transport mechanisms for hepatic uptake
and biliary secretion of these compounds. This is the first direct
demonstration of an enterohepatic circulation for a bile alcohol
sulfate in fish liver.
cholyltaurine; bile alcohol transport; bile acid transport; liver
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