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Received for publication January 25, 2005.
Revised April 4, 2005.
Accepted for publication April 6, 2005.
The Multidrug resistance-associated proteins (Mrp) are
ATP-dependent transporters that export a variety of
conjugated and unconjugated compounds out of cells.
There are nine identified Mrp transporters in humans,
with murine orthologues for all except Mrp8. Because
nuclear receptors mediate induction of phase-I enzymes,
Mrp transporter expression might be similarly regulated
by these receptors to coordinate metabolism and export
of chemicals from liver. To test the hypothesis that
Mrp expression may be coordinately regulated with phase-
I enzyme expression in liver, 15 different compounds
were given representing known transcriptionally-mediated
pathways: aryl hydrocarbon receptor (AhR), pregnane-X-
receptor (PXR), constitutive androstane receptor (CAR),
peroxisomal proliferator-activated receptor 
(PPAR),
and NF-E2-related factor 2 (Nrf2). Each of these
compounds induced expression of their respective target
enzyme in liver, demonstrating that the chemical
regimens were effective. The AhR ligands (TCDD, PCB126,
and 
-naphthoflavone) induced Mrp2, 3, 5 and 6 mRNA
expression. The CAR activator TCPOBOP induced Mrp2, 3,
4, 6 and 7 mRNA expression. Mrp3 was also induced by
two other CAR activators phenobarbital and diallyl
sulfide, two PXR ligands, pregnenalone-16-carbonitrile
and spironolactone, and the PPAR ligands clofibrate,
ciprofibrate, and diethylhexylphthalate. The Nrf2
activators (butylated hydroxyanisole, oltipraz, and
ethoxyquin) induced Mrp2-6. A variety of mechanisms are
suggested for Mrp3 induction, including AhR, CAR, PXR,
PPAR, and Nrf2, whereas on a whole, a predominant role
for AhR and Nrf2 in hepatic induction of the Mrp family
was observed. Thus these specific transcription factors
are implicated in regulation of both drug metabolism and
efflux transport.
Key words:
ABC transporters, drug interactions, drug transport, gene regulation, hepatobiliary disposition, hepatobiliary transport, membrane structure
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