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Vol. 300, Issue 1, 206-212, January 2002
Department of Pharmacology, Toxicology and Therapeutics, University
of Kansas Medical Center, Kansas City, Kansas
Knowledge of regulation of transporters would aid in predicting
pharmacokinetics and drug-drug interactions. Treatment of rats with
pregnenolone-16
-carbonitrile (PCN) and phenobarbital increases
hepatic uptake of cardiac glycosides. Rat organic anion transporting
polypeptide 2 (oatp2; Slc21a5) transports cardiac glycosides with high
affinity. Levels of rat hepatic oatp2 protein and mRNA are regulated by
PCN and phenobarbital treatment; however, the effects of other
microsomal enzyme inducers on oatp2 have not been investigated.
Therefore, the purpose of this study was to further determine whether
oatp2 is regulated by a broader scale of drug-metabolizing enzyme
inducers that are ligands or activators for the aryl hydrocarbon
receptor (AhR), constitutive androstane receptor (CAR), pregnane X
receptor (PXR), peroxisome proliferator-activated receptor (PPAR), and
antioxidant/electrophile response element (ARE/EpRE). Oatp2 protein
levels determined by Western blot were decreased 56 to 72% by the AhR
ligands, increased 84 to 132% by the CAR ligands, and increased 230 to
360% by PXR ligands. The PPAR ligands and ARE/EpRE activators
generally had minimal effects on oatp2 protein levels. Oatp2 mRNA
levels, determined by the bDNA technique, generally did not show a
correlation with the altered oatp2 protein levels, e.g., among PXR
ligands, only PCN increased oatp2 mRNA levels, but spironolactone and
dexamethasone did not. Furthermore, only PCN, but not spironolactone
and dexamethasone, increased the transcription of the oatp2 gene as the
amount of hnRNA was increased when determined by reverse
transcription-polymerase chain reaction. In conclusion, some
drug-metabolizing enzyme inducers regulate oatp2 protein levels,
especially the CYP3A inducers. However, there is no correlation between
their ability to increase levels of oatp2 protein and mRNA, suggesting
that regulation of oatp2 by drug-metabolizing enzyme inducers occurs at
both the transcriptional and post-translational levels.
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