BILE ACID TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 213

GR, the relative locations and configurations of the GR response elements within the
two promoters are not conserved.

9.7. CROSSTALK BETWEEN THE TRANSCRIPTIONAL CONTROL
OF BILE ACID AND DRUG TRANSPORTERS

Transport and metabolism of exogenous compounds, such as drugs, nutrients, and
environmental xenobiotics, bear many similarities to those of endogenous bile acids.
Indeed, drugs may undergo enterohepatic circulation similarly to bile acids. Several
transporters recognize both bile acids and drugs as substrates. For example, although
their significance for overall bile acid transport in normal physiology remains uncer-
tain, the two transporters of the human OATP1B subfamily, OATP1B1 and OATP1B3,
can transport bile acids in addition to drugs such as methotrexate and rifampicin. 103
The transcriptional regulatory circuits controlling the expression of drug transporter
genes often contain feedforward and feedback loops reminiscent of the mechanisms
outlined for regulation of bile acid transport above (reviewed in ref. 76). It is becoming
increasingly apparent that in addition to reprogramming of genes involved in bile acid
homeostasis, changes in intracellular concentrations of bile acids also influence the
expression levels of hepatic and intestinal drug transporters. Thus, changes in intra-
cellular bile acid levels may affect the efficiency of drug extraction and elimination.
HNF4 is a liver-enriched nuclear receptor with a critical role in maintaining the

hepatic pattern of gene expression. 104 It binds to the DNA response elements on its
target promoters, preferably of the DR-1 or DR-2 configuration, as homodimers. The
ligand-binding domain of HNF4

has been suggested to be bound constitutively by
endogenous fatty acids 105 , 106 ; thus, its activity may not be modulated readily by exoge-
nous ligands. In addition to its previous roles in regulation of glucose and cholesterol
metabolism, HNF4

has recently emerged as a regulator of hepatic drug transport
in humans. The genes encoding two major hepatic basolateral drug transporters in
humans, organic anion transporter 2 (OAT2; SLC22A7 ) 107 and organic cation trans-

porter 1 (OCT1; SLC22A1 ), 108 . OAT2 mediates uptake

of drugs such as salicylates and cephalosporins from sinusoidal blood, whereas OCT1
transports dopamine, metformin, and verapamil, among other substrates.
In the regulatory regions of the human SLC22A7 gene, HNF4

are transactivated by HNF4

transactivation is
mediated by a single DR-1 element. The human SLC22A1 promoter, in turn, contains
two adjacent lower-affinity DR-2 elements, both of which are required for maximal
transactivation by HNF4

. In both promoter contexts, the bile acid-induced tran-
scriptional repressor SHP interferes with transactivation by HNF4 . It thus appears

that in conditions of elevated intracellular bile acid concentrations, the expression
of two major drug uptake systems at the basolateral hepatic membrane is reduced.
This could limit the amount of xenobiotics that enters the hepatocyte for subsequent
metabolism when intracellular levels of toxic bile acids are already elevated. Also,
the possibility of decreased hepatic extraction of drugs that are substrates of OAT2
and OCT1 should be taken into account when such drugs are administered to patients
suffering from cholestasis.