Rat PXR Reporter-Gene Activity Correlates with the Induction of CYP3A in Rat Precision-Cut Liver Slices

Author(s): Xiaoming Cui, Ann Thomas, Diana Montgomery, Chunyan Gu, Richard A. Morrison, Ronald E. White, K. -C. Cheng

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 8 , Issue 4 , 2005

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Recent studies have suggested that both constitutive androstane receptor (CAR) and pregnane Xreceptor (PXR) are involved in the induction of rat liver microsomal cytochrome P-450 (CYP) 2B and 3A through a mechanism called cross-talk. In this study we intend to determine if a PXR-reporter gene assay could be used for the prediction of CYP3A and/or CYP2B induction in rats. The induction of rat CYP2B and CYP3A by nineteen structurally diverse compounds was evaluated by using rat precision-cut liver slices and a rat PXR reporter-gene system. Induction of CYP2B and CYP3A mRNAs in rat liver slices was quantified by real-time polymerase chain reaction. Rat PXR activation was measured by induction of luciferase activity in rat PXR reporter-gene system. Linear regression analysis of the fold of induction of mRNA in liver slices and the fold of luciferase activity in rat PXR reporter-gene system shows that a reasonable correlation (r2=0.6) exists between the CYP3A induction and the rat PXR activation. A much lower correlation was observed between CYP2B induction and the rat PXR activation (r2=0.1). The results from this study suggest that the PXR may play a major role in the induction of rat CYP3A, but not CYP2B. Therefore, the PXR-reporter gene assay may be useful in a high-throughput screening to predict CYP3A induction in rats.

Keywords: cypb, cypa, induction, pxr, and liver slice

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Article Details

Year: 2005
Page: [341 - 346]
Pages: 6
DOI: 10.2174/1386207054020822
Price: $65

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