Effect of prototypical inducers on ligand activated nuclear receptor regulated drug disposition genes in rodent hepatic and intestinal cells |
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Authors: | Philip MARTIN Robert RILEY Paul THOMPSON Dominic WILLIAMS David BACK Andrew OWEN |
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Affiliation: | [1]Department of Pharmacology and Therapeutics, The University of Liverpool, Pembroke Place, Liverpool, L69 3GF, UK [2]Department of Physical and Metabolic Science, AstraZeneca Charnwood, Leicestershire, LE11 5RH, UK [3]School of Biomedical Sciences, The University of Ulster, Cromore Road, Coleraine, Co. Londondarry, BT52 1SA, UK |
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Abstract: | Aim:The aim of this study was to investigate the impact on expression of mRNA and protein by paradigm inducers/activators of nuclear receptors and their target genes in rat hepatic and intestinal cells. Furthermore, assess marked inter laboratory conflicting reports regarding species and tissue differences in expression to gain further insight and rationalise previously observed species differences between rodent and human based systems.Methods:Quantitative real time-polymerase chain reaction (QRT-PCR) and immunoblots were used to assess messenger RNA (mRNA) and protein expression for CYP2B2, CYP3A1, CYP3A2, CYP3A9, ABCB1a, ABCB1b, ABCC1, ABCC2, pregnane X receptor (PXR), farnesoid X receptor (FXR) and constituitive androstane receptor (CAR) in rat hepatoma cell line H411E, intestinal cells, Iec-6, and rat primary hepatocytes, in response to exposure for 18 h with prototypical inducers.Results:Dexamethasone (DEX) and pregnenolone 16α carbonitrile (PCN) significantly induced PXR, CYP3A9, ABCB1a and ABCB1b. However, when co-incubated, DEX appeared to restrict PCN-dependent induction. Chenodeoxycholic acid (CDCA) was the only ligand to induce FXR in all three cell types. Despite previously reported species differences between PCN and rifampicin (RIF), both compounds exhibited a similar profile of induction.Conclusion:Data presented herein may explain some of the discrepancies previously reported with respect to species differences from different laboratories and have important implications for study design. |
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Keywords: | nuclear receptors hepatic cells intestinal cells prototypical inducers rodents dexamethasone pregnenolone 16α carbonitrile cytochrome P450 pregnane X receptor constituitive androstane receptor |
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