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  • Title: Hepatocellular bile acid transport and ursodeoxycholic acid hypercholeresis.
    Author: Scharschmidt BF, Lake JR.
    Journal: Dig Dis Sci; 1989 Dec; 34(12 Suppl):5S-15S. PubMed ID: 2689116.
    Abstract:
    This review focuses on mechanisms of bile acid transport across the basolateral and canalicular hepatocyte plasma membranes and on ursodeoxycholic acid (UDCA) hypercholeresis and biotransformation. Conjugated trihydroxy bile acids enter hepatocytes via a sodium-coupled mechanism localized to the basolateral membrane, which is saturable, concentrative, inhibited by other bile acids as well as by furosemide and bumetanide, and exhibits developmental changes in rats and probably also in humans. The stoichiometry of sodium-coupled bile acid uptake has been controversial. Hydrophobic, unconjugated dihydroxy and monohydroxy bile acids, including UDCA, enter hepatocytes more rapidly than does taurocholate, and their uptake is largely nonsaturable and sodium independent. A hydroxyl-exchange mechanism that mediates the uptake of cholic acid has also been reported, but its existence is controversial. Current evidence suggests that a 49-kDa protein mediates Na+-dependent taurocholate uptake and that a 54-kDa protein is involved in Na+-independent bile acid uptake. Studies with canalicular membrane vesicles have demonstrated saturable, sodium-independent taurocholate transport, which is sensitive to electrical potential, exhibits trans-stimulation, and appears to be mediated by a 100-kDa canalicular membrane glycoprotein. Studies in mutant rats with conjugated hyperbilirubinemia suggest the presence of a separate canalicular transport mechanism utilized by sulfated bile acids and organic anions such as bilirubin and sulfobromophthalein. UDCA produces in some species a dramatic hypercholeresis that is greater than expected based on the osmotic effect of the secreted bile acid. The hypercholeresis appears attributable to stimulation of biliary bicarbonate output and is decreased or abolished in the perfused rat liver by amiloride or perfusate Na+ substitution. These same maneuvers dramatically alter UDCA biotransformation (unconjugated UDCA disappears from bile, and UDCA glucuronide becomes a major metabolite) and lower hepatocyte intracellular pH. These and other findings indicate that UDCA hypercholeresis is tightly linked to biliary excretion of the unconjugated species and suggest that UDCA biotransformation may be influenced by intracellular pH.
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