M. Muller et Plm. Jansen, MOLECULAR ASPECTS OF HEPATOBILIARY TRANSPORT, American journal of physiology: Gastrointestinal and liver physiology, 35(6), 1997, pp. 1285-1303
Generation of bile flow is a regulated, ATP-dependent process and depe
nds on the coordinated action of a number of transporter proteins in t
he sinusoidal and canalicular domains of the hepatocyte. Dysfunction o
f any of these proteins leads to retention of substrates, with conjuga
ted hyperbilirubinemia or cholestasis as a result. In recent years man
y of the transport proteins involved in bile formation have been ident
ified, cloned, and functionally characterized. The hepatocyte sinusoid
al membrane contains transport proteins for the hepatic uptake of orga
nic anions and cations and for the uptake of bile acids. The multispec
ific organic anion transporting polypeptide (OATP) mediates the hepati
c uptake of organic anions and a variety of organic amphiphilic compou
nds, including organic cations. The organic cation transporter OCT1 mo
re specifically transports small organic cations. NTCP is the Na+-bile
acid cotransporting protein that mediates the hepatic uptake of bile
acids. The canalicular transport proteins are able to transport endoge
nous and exogenous metabolites into the bile against steep concentrati
on gradients. Most of these transporters are members of the large ATP-
binding cassette (ABC) superfamily, and their transport function direc
tly depends on the hydrolysis of Mg2+/ATP. At least five ABC transport
er proteins have been characterized so far: I) the human multidrug res
istance protein MDR1 mediates the excretion of hydrophobic, mostly cat
ionic, metabolites; 2) MDR3 is involved in phosphatidylcholine secreti
on; 3) the canalicular bile acid transporter cBAT mediates secretion o
f monovalent bile salts and provides the molecular basis of bile acid-
dependent bile flow; 4) SPGP, product of the P-glycoprotein sister gen
e, is exclusively expressed in the liver but its function is currently
unknown; and 5) the human multidrug resistance protein MRP2 mediates
the excretion of multivalent anionic conjugates.