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Vol. 31, Issue 5, 523-527, May 2003
Department of Pharmacology Pregnane X receptor (PXR) and constitutive androstane receptor
(CAR) are key regulators of xenobiotic-inducible cytochrome P450
gene expression. Whereas much is known about their role in regulating
drug metabolism, little is known regarding their role in regulating
drug transport in vivo. Wild-type mice and mice lacking PXR (PXR-KO)
were used to examine the inducible expression of two drug transporter
genes, Oatp2 (Slc21a5) and
Mrp3 (Abcc3), in liver following
treatment with selective PXR and CAR activators. Selective activation
of PXR or CAR induced Oatp2 and Mrp3
expression in wild-type mice but not in PXR-KO mice. Basal expression
levels of Oatp2 and Mrp3 gene were
significantly higher in PXR-KO mice when compared with wild-type mice.
Additionally, phenobarbital (PB)-inducible Oatp2 and
Mrp3 gene expression was significantly increased in the
PXR-KO mice when compared with wild-type PB-treated mice. We also
examined the effect of PXR ablation on PB-inducible hepatic CYP3A
activity in vivo. Microsomes isolated from PB-treated PXR-KO mice
exhibited a significantly elevated rate of testosterone 6
and Toxicology,
University of
Kansas,
Lawrence, Kansas (J.L.S.);
and XenoTech LLC,
Lenexa, Kansas
(A.M., K.M.C., A.P.)
-hydroxylation when compared with microsomes isolated from
wild-type PB-treated mice. PB treatment produced significantly
increased levels of hepatomegaly in PXR-KO mice when compared with
wild-type PB-treated mice. Taken together, these results suggest that
nonliganded PXR plays a net negative role in coregulating shared
PXR/CAR-target gene expression in vivo and extend the hypothesis that
PXR and CAR coregulate not only drug metabolism but also drug transport.
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