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J Pharmacol Exp Ther. 2018 Feb 12. pii: jpet.117.247296. doi: 10.1124/jpet.117.247296. [Epub ahead of print]

Establishing Transcriptional Signatures to Differentiate PXR-, CAR- and AhR-Mediated Regulation of Drug Metabolism and Transport Genes in Cryopreserved Human Hepatocytes.

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Pfizer Worldwide Research and Development
Pfizer Worldwide Research and Development.


The potential for drug-drug interactions (DDIs) arising from transcriptional regulation of drug disposition genes via activation of nuclear receptors (NRs) such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), and/or aryl hydrocarbon receptor (AhR) remains largely unexplored, as highlighted in a recent guidance document from the European Medicines Agency. The goal of this research was to establish PXR/CAR/AhR-specific drug metabolizing enzyme (DME) and transporter gene expression signatures in sandwich-cultured cryopreserved human hepatocytes using selective activators of PXR (rifampin), CAR (CITCO) and AhR (omeprazole). Dose response for ligand-induced changes to 35 major human DMEs and critical hepatobiliary transporters were assessed using a custom gene expression array card. We identified novel differentially expressed drug disposition genes for PXR (↑ABCB1/MDR1, CYP2C9, CYP2C19 and EPHX1, ↓ABCB11), CAR (↑SULT1E1, UGT2B4) and AhR (↑SLC10A1/NTCP, SLCO1B1/OATP1B1), and co-regulated genes (CYP1A1, CYP2B6, CYP2C8, CYP3A4, UGT1A1, UGT1A4). Subsequently, DME gene expression signatures were generated for known CYP3A4 inducers, PF-06282999 and pazopanib. The former produced an induction signature almost identical to rifampin, suggesting activation of the PXR pathway; whereas the latter produced an expression signature distinct from those of PXR, CAR or AhR, suggesting involvement of an alternate pathway(s). These results demonstrate that involvement of PXR vs. CAR vs. AhR can be identified via expression changes of signature DME and transporter genes. Inclusion of such key signature genes in could serve to simultaneously identify potential inducers and inhibitors, and the NRs involved in the transcriptional regulation, thus providing a more holistic and mechanism-based assessment of DDI risk.


CAR; Pregnane X Receptor; aryl hydrocarbon receptors (AHR); drug metabolism; drug transport

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