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Vol. 289, Issue 3, 1592-1599, June 1999
Division of Drug Delivery and Disposition, School of Pharmacy,
University of North Carolina, Chapel Hill, North Carolina
Previous work in our laboratory has indicated that biliary excretion of
a substrate in sandwich-cultured hepatocytes can be quantitated by
measurement of substrate accumulation in the presence and absence of
extracellular Ca2+. The present study was designed to
examine the effects of Ca2+ on taurocholate accumulation
and tight junction integrity in cultured hepatocytes. Kinetic modeling
was used to characterize taurocholate disposition in the hepatocyte
monolayers in the presence and absence of extracellular
Ca2+. The accumulation of taurocholate in freshly isolated
hepatocytes, which lack an intact canalicular network, was the same in
the presence and absence of extracellular Ca2+. Electron
microscopy studies showed that Ca2+ depletion increased the
permeability of the tight junctions to ruthenium red, demonstrating
that tight junctions were the major diffusional barrier between the
canalicular lumen and the extracellular space. Cell morphology and
substrate accumulation studies in the monolayers indicated that
Ca2+ depletion disrupted the tight junctions in 1 to 2 min.
The integrity of the disrupted tight junctions was not re-established
completely after reincubation in the presence of Ca2+ for
1 h. The accumulation of taurocholate was described best by a
two-compartment model (cytosol and bile) with Michaelis-Menten kinetics
for both uptake and biliary excretion. In summary, Ca2+
depletion does not alter hepatocyte transport properties of
taurocholate. Ca2+ modulation may be a useful approach to
study biliary excretion of substrates in sandwich-cultured hepatocytes.
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