Establishing Transcriptional Signatures to Differentiate PXR-, CAR-, and AhR-Mediated Regulation of Drug Metabolism and Transport Genes in Cryopreserved Human Hepatocytes
Autor: | Theunis C. Goosen, Nathaniel Johnson, Jamie E. Moscovitz, Yan Weng, Amit S. Kalgutkar, Kelly Nulick, Zhiwu Lin |
---|---|
Rok vydání: | 2017 |
Předmět: |
Transcriptional Activation
CYP2B6 Transcription Genetic Receptors Cytoplasmic and Nuclear digestive system 030226 pharmacology & pharmacy Xenobiotics 03 medical and health sciences 0302 clinical medicine Constitutive androstane receptor Gene expression Transcriptional regulation Humans Receptor Constitutive Androstane Receptor Pharmacology Cryopreservation Pregnane X receptor biology Chemistry Pregnane X Receptor Biological Transport Aryl hydrocarbon receptor Cell biology Nuclear receptor Pharmaceutical Preparations Receptors Aryl Hydrocarbon 030220 oncology & carcinogenesis biology.protein Hepatocytes Molecular Medicine |
Zdroj: | The Journal of pharmacology and experimental therapeutics. 365(2) |
ISSN: | 1521-0103 |
Popis: | 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 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 38 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 [↑sulfotransferase (SULT) 1E1, uridine glucuronosyl transferase (UGT) 2B4], and AhR (↑SLC10A1/NTCP, SLCO1B1/OATP1B1], and coregulated 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 that of 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/CAR/AhR can be identified via expression changes of signature DME/transporter genes. Inclusion of such signature genes 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 for DMEs and transporters beyond conventional cytochrome P450 isoforms. |
Databáze: | OpenAIRE |
Externí odkaz: |