Regulation of drug transporter gene expression by nuclear receptors.
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 beta-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.
Staudinger
Jeff L
JL
Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas 66045, USA. stauding@ku.edu
Madan
Ajay
A
Carol
Kathleen M
KM
Parkinson
Andrew
A
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000235:genetics; D001692:Biological Transport; D015152:Blotting, Northern; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D005786:Gene Expression Regulation; D006529:Hepatomegaly / Q000139:chemically induced / Q000473:pathology; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis* / Q000235:genetics; D009929:Organ Size; D027701:Organic Cation Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis* / Q000235:genetics; D010634:Phenobarbital; D016133:Polymerase Chain Reaction; D000077297:Pregnane X Receptor; D020239:Receptor Cross-Talk; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*; D013739:Testosterone / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D001189:Aryl Hydrocarbon Hydroxylases; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027701:Organic Cation Transport Proteins; D010089:Oxidoreductases, N-Demethylating; D010634:Phenobarbital; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013739:Testosterone; D014157:Transcription Factors; C464433:Oatp2 protein, mouse; C114462:multidrug resistance-associated protein 3