ABSTRACT
The vectorial secretion of bile salts from blood into bile is a major driving force
for bile formation. The basolateral hepatocyte membrane extracts bile salts from sinusoidal
blood via Na+-dependent and Na+-independent membrane transporters. Na+-dependent uptake of bile salts is mediated by the Na+-taurocholate cotransporting polypeptide, a 51-kDa protein that is exclusively expressed
in hepatocytes. Na+-independent uptake of bile salts is mediated by the organic anion transporting polypeptides,
a superfamily of multispecific bile salt and amphipathic substrate transporters. Within
the hepatocyte, bile salts are bound to cytosolic proteins and traverse the cell mainly
by diffusion. Transport across the canalicular membrane is the rate-limiting step
in overall hepatocellular bile salt excretion and is mediated by the bile salt export
pump (BSEP), a homologue of the P-glycoproteins or multidrug resistance gene products.
BSEP is a vulnerable target for inhibition by estrogen metabolites, drugs such as
cyclosporine A, and abnormal bile salt metabolites, all of which can cause retention
of bile salts and consequently intrahepatic cholestasis. Canalicular efflux of divalent
sulfated or glucuronidated bile salts is mediated by the multidrug resistance protein
2 (MRP2), which is strongly decreased in cholestasis. Decreased MRP2 expression leads
to compensatory increases in the basolateral expression of MRP1 and MRP3, which mediate
the sinusoidal efflux of divalent bile salt conjugates and other organic anions. Thus,
the hepatocyte can regulate expression levels of individual bile salt transporters
during cholestasis to evade hepatotoxic injury.
KEYWORD
organic anions - bile acid transport - cholestasis
