BILE ACID TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 204

notably phosphatidylcholine, and cholesterol. Phospholipids are translocated from
the inner to the outer leaflet of the canalicular membranes of hepatocytes by yet
another ABC transporter, the multidrug resistance protein 3 (MDR3, ABCB4 ). 5 The
transport system for cholesterol at the canalicular membrane of hepatocytes is the
protein heterodimer ABCG5/ABCG8. 7 The efflux of lipids mediated by MDR3 and
ABCG5/ABCG8 promotes the formation of mixed micelles containing bile acids,
cholesterol, and phospholipids. This process not only solubilizes cholesterol but also
helps to protect cholangiocytes against the harmful detergent effects of bile acids in
the biliary tree.
After their passage to the intestinal lumen, bile acids are efficiently taken up into
ileocytes via the apical sodium-dependent bile acid transporter (ASBT, SLC10A2 ). 8
Characteristic of the SLC10 (solute carrier) family of transporters, 9 ASBT contains
seven transmembrane domains, and its bile acid uptake activity is electrogenically
coupled with cotransport of sodium.
It has been proposed that transcellular shuttling of bile acids from the apical mem-
brane domain of enterocytes to the basolateral membrane may be facilitated by the
small cytosolic protein called the ileal bile acid-binding protein (I-BABP). 10 , 11 It has
been suggested that I-BABP interacts physically with ASBT, 12 although the functional
significance of this interaction remains unclear.
At the basolateral membrane domain of ileal enterocytes, bile acids are extruded
into portal blood by the heterodimeric organic solute transporter OST . 13 The /OST

OST protein is predicted to contain seven membrane-spanning domains, whereas the

smaller subunit OST

has a single transmembrane domain. Coexpression of OST

and OST polypeptides is required for correct localization of the heterodimer at the

cell membrane and for transport activity. Consistent with its role as the intestinal
bile acid efflux transporter, distribution of the OST heterodimer along the

intestine closely mirrors that of the bile acid uptake system ASBT.
Finally, to complete the enterohepatic circulation, bile acids are extracted from
the portal blood circulation by the liver. The sodium-taurocholate cotransporting
polypeptide (NTCP, SLC10A1 ) at the sinusoidal membrane of hepatocytes is the chief
uptake system for bile acids from portal blood into the parenchymal cells of the liver. 14
NTCP belongs to the same sodium-dependent SLC10 transporter family as ASBT,
and is similarly likely to contain seven transmembrane domains and a cytoplasmic
carboxy terminus. 9 , 15 The amino acid identity between the human NTCP and ASBT
is approximately 35%.
While NTCP is responsible for the sodium-dependent uptake of bile acids
into hepatocytes, certain members of the organic anion transporter (OATP, SLCO )
family, notably OATP1B1 (gene symbol SLCO1B1 ; previously known as OATP-
C/OATP2/ SLC21A6 ), may also contribute to bile acid extraction from the portal blood
at the basolateral membrane of hepatocytes in a sodium-independent manner. 16
Under normal physiological conditions, only negligible amounts of bile acids are
effluxed back to portal blood at the basolateral hepatocyte membrane. However, in
cholestatic states, the expression of the two basolateral bile acid overflow systems
of the ABC transporter family, multidrug resistance-associated proteins 3 (MRP3,
ABCC3 ) and 4 (MRP4, ABCC4 ), is increased. 17 - 19

/OST

Thus, in cholestasis, MRP3 and