Rat pregnane X receptor: Molecular cloning, tissue distribution, and xenobiotic regulation

An orphan nuclear receptor, termed the pregnane X receptor (PXR), has recen tly been cloned from mouse and human and defines a novel steroid signaling pathway (Cell 92, 73-82, 1998; Proc. Natl. Acad. Sci. USA 95, 12208-122313, 1998). Transient cotransfection experiments demonstrate that the PXR respo nds to structurally dissimilar compounds and confers the induction of cytoc hrome P4503A (CYP3A), a subfamily of enzymes that involve the metabolism of two-thirds of drugs and other xenobiotics. In this report, we describe the molecular cloning, tissue distribution, and xenobiotic regulation of a rat PXR designated rPXR-1. rPXR-1 exhibits a 95% sequence identity with the mo use PXR, but only 79% identity with the human PXR, providing the molecular basis that rats and mice have a similar CYP3A induction profile but differ from humans. rPXR-1 gene was expressed abundantly in liver, intestine, and, to a lesser extent, kidney, lung, and stomach. The tissue distribution and the relative abundance of rPXR-1 mRNA among these tissues resemble those o f CYP3A, suggesting that PXR is important not only for induction but also f or constitutive expression of these enzymes. Xenobiotics known to induce li ver microsomal enzymes showed differential effects on the rPXR-1 expression as determined by Northern blot analysis. Dexamethasone, for example, incre ased the accumulation of rPXR-1 mRNA, whereas troleandomycin slightly suppr essed it. Compounds that increase PXR expression (inducers) and compounds t hat interact with PXR (ligands) likely have synergistic effects on CYP3A in duction, which provides a novel molecular explanation for drug-drug interac tions. (C) 1999 Academic Press.