BILE ACID TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 205

MRP4 may transport substantial amounts of bile acids from hepatocytes back into the
systemic circulation for subsequent renal excretion. In addition to MRP3 and MRP4,
OST are also expressed at the basolateral membranes of hepatocytes in

humans. 20 It is thus conceivable that OST

and OST

/OST may also contribute to alternative

bile acid efflux during cholestasis.
Similar to I-BABP in enterocytes, proteins that are involved putatively in intracel-
lular trafficking of bile acids from the basolateral to the canalicular membrane have
been identified in hepatocytes. 21 , 22 One such intracellular protein capable of binding
bile acids with a high affinity in the human liver is the hepatic bile acid-binding
protein (HBAB), which may thus assist in the rapid transcellular vectorial transport
of bile acids in hepatocytes. 23

9.3. ENTEROHEPATICBILEACIDTRANSPORTERS INLIVERDISEASE

Chronic cholestatic liver diseases such as primary biliary cirrhosis and primary scle-
rosing cholangitis are characterized by an impairment of bile formation or of bile
flow. Altered expression or function of bile acid transporters can be either a cause or a
consequence of cholestasis, thus leading to hepatotoxicity due to accumulation of bile
acids and cholephilic toxins in hepatocytes. Among the genes encoding transporters
that are involved in bile acid transport or bile formation are several that have been
identified or proposed as disease genes in the pathogenesis of cholestasis.
Progressive familial intrahepatic cholestasis type 2 (PFIC2) is caused by mutations
in the ABCB11 gene, which encodes BSEP. 24 , 25 These mutations in the ABCB11 gene
lead to a rapidly progressive hepatic dysfunction in early infancy. In such patients the
biliary bile salt levels can be reduced to less than 1% that of normal subjects. In a recent
case report, specific ABCB11 mutations identified in an adolescent cholestatic patient
correlated with reduced BSEP protein expression in vivo and decreased bile acid trans-
port activity in vitro. 26 Another case report suggested that heterozygous BSEP defi-
ciency may predispose to transient neonatal cholestasis. 27 Furthermore, defective or
altered function or expression of BSEP may contribute to certain types of drug-induced
cholestasis 28 and may be associated with intrahepatic cholestasis of pregnancy. 29
Defective MDR3 expression has also been associated with the inherited liver dis-
ease PFIC, type 3. 30 , 31 PFIC3 is characterized by high bile acid concentrations and

elevated -glutamyl transpeptidase activity in serum. Several PFIC3-associated mu-

tations in the ABCB4 gene may lead to either absent or severely decreased MDR3
expression at the canalicular membrane of hepatocytes. Similar to BSEP, there is
increasing evidence suggesting that deficiency of impaired activity of MDR3 may be
involved in cholestasis induced by drugs such as oral contraceptives. 32 , 33
Inherited mutations in the ABCC2 gene encoding the canalicular transporter MRP2
are linked to the Dubin-Johnson syndrome, characterized by reduced efflux of con-
jugated bilirubin into bile. 34 − 37 Some of these mutations have been reported to result
in an absence of the MRP2 protein from the canalicular membrane of hepatocytes. In
contrast to the PFIC syndromes, hepatic function is preserved in the Dubin-Johnson
syndrome.