MOLECULAR ASPECTS OF HEPATOBILIARY TRANSPORT

Citation
M. Muller et Plm. Jansen, MOLECULAR ASPECTS OF HEPATOBILIARY TRANSPORT, American journal of physiology: Gastrointestinal and liver physiology, 35(6), 1997, pp. 1285-1303
Citations number
241
Categorie Soggetti
Physiology
ISSN journal
01931857
Volume
35
Issue
6
Year of publication
1997
Pages
1285 - 1303
Database
ISI
SICI code
0193-1857(1997)35:6<1285:MAOHT>2.0.ZU;2-J
Abstract
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.