DRUG TRANSPORT IN THE LIVER - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 372

Cytokine-mediated inflammatory cholestasis causes down-regulation of Ntcp and
Mrp2 by the RAR (retinoic acid receptor) and RXR heterodimer. 71 SLCO1B3 gene
expression has been reported to be regulated by the bile acid chenodeoxycholic acid
(CDCA), which is a ligand of FXR/BAR (farnesoid X receptor/bile acid receptor).
This provides another mechanism for decreased hepatic uptake of bile acids during
cholestatic stress. 72
The canalicular protein Bsep contains a promoter region sequence specific for
binding of the FXR nuclear receptor, after heterodimerization with RXR . When this

complex is bound by bile acids, it effectively regulates the transcription of several
genes involved in bile acid homeostasis. 73 PXR induces CYP3A4 and P-glycoprotein
by similar mechanisms in the human colon carcinoma cell line LS174T; the promoter
region of the MDR1 gene contains a DR4 motif to which PXR binds. 74 PXR also
mediates the induction of MRP1 and MRP2 through redox-active compounds. How-
ever, the role of PXR is still unclear because deletion of the binding sites that are
hypothesized to mediate the induction process did not result in a significant decrease
in induction. 75 Mrp2 mRNA levels were induced following treatment with natural
and synthetic FXR ligands; in PXR null and wild-type mice, Mrp2 was induced by
the PXR activators, dexamethasone, pregnenolone 16

-carbonitrile, and the CAR

agonist phenobarbital. 76

In mice, Mdr2 mRNA and protein are induced by PPAR ,

which is a nuclear receptor activated by fatty acids and hypolipidaemic fibrates. 77

13.6. DISEASE STATE ALTERATIONS IN HEPATIC
TRANSPORT PROTEINS

Many genetic mutations influence transport protein expression, localization, and/or
function. For example, Dubin-Johnson syndrome is a rare autosomal recessive liver
disorder in humans characterized by chronic conjugated hyperbilirubinemia that is due
to the absence of MRP2 on the canalicular membrane. 78 Similar mutations have been
found in the Mrp2 gene in TR − (transport deficient) Wistar rats and EHBR (Eisai
hyperbilirubinemic) Sprague-Dawley rats. One compensatory mechanism for the
absence of MRP2/Mrp2 protein in patients with Dubin-Johnson syndrome and EHBR
and TR − rats is increased expression of MRP3/Mrp3 on the basolateral membrane. 30
Progressive familial intrahepatic cholestasis (PFIC), primarily a childhood dis-
ease that affects canalicular bile transport, is classified into three different types.
PFIC type 1 is caused by a mutation in the gene encoding the familial intrahepatic
cholestasis 1 protein (FIC1). This protein plays a role in maintaining bile salt hom-
eostasis. PFIC types 2 and 3 are caused by mutations in the genes encoding BSEP
and the phospholipid translocase (MDR3), respectively. Benign recurrent intrahepatic
cholestasis (BRIC), or recurrent familial intrahepatic cholestasis (RFIC), a very rare
disease that affects only a few hundred patients worldwide, involves a mutation in the
FIC1 gene, similar to PFIC type 1. 79
There are also many forms of acquired defects in bile salt transport that involve
direct inhibition of function or expression of the bile salt transport proteins result-
ing in cholestasis, including drug-induced cholestasis, sepsis-associated cholestasis,