Induction Profile of Rat Organic Anion Transporting polypeptide 2 (oatp 2) by Prototypical Drug-Metabolizing Enzym Inducers That Activate Gene Expression through Ligand-Activated Transcription Factor Pathways

摘要

Knowledge of regulation of transporters would aid in predicting pharmacokinetics and drug-drug interactions. treatment of rats with pregnenolone-16#alpha#-carbonitrile(PCN)and phenobarbital increases hepatic uptake of cardiac glycosides. Rat organic an8on transporting polypeptide 2 (oatp2;Slc215)transports cardiac glycosides with high affinity. Levels of rat hepatic oatp2 protein and mRNA are regulated by PCN and pheobarbital 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), receptor(PPAR), and antioxidant/electrophile response element(ARE/EpRE), Oatp2 protein levels determined by Western blot were deceased 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 MPNA levels. But spironolactone and dexamethasone did not. Furthermore, only PCN, but not spironolactone and dexamethasone, increased the trascription 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 transcriptional and post-translational levels