Control of Steroid, Heme, and Carcinogen Metabolism by Nuclear Pregnane X Receptor and Constitutive Androstane Receptor
Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor Wen Xie*†‡, Mei-Fei Yeuh‡§, Anna Radominska-Pandya¶, Simrat P. S. Saini*, Yoichi Negishi*, Bobbie Sue Bottroff†, Geraldine Y. Cabrera†, Robert H. Tukey§, and Ronald M. Evans†ʈ *Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213; †Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037; §Laboratory of Environmental Toxicology, Departments of Chemistry, and Biochemistry and Pharmacology, University of California at San Diego, La Jolla, CA 92093; and ¶Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 Contributed by Ronald M. Evans, December 31, 2002 Through a multiplex promoter spanning 218 kb, the phase II UDP- ogens, estrogen, and thyroxin metabolism. Moreover, activation of glucuronosyltransferase 1A (UGT1) gene encodes at least eight dif- PXR in transgenic mice is sufficient to increase levels of UGT ferently regulated mRNAs whose protein products function as the expression and activity, as well as bilirubin and steroid clearance. principal means to eliminate a vast array of steroids, heme metabo- lites, environmental toxins, and drugs. The orphan nuclear receptors Materials and Methods pregnane X receptor (PXR) and constitutive androstane receptor Animals. The generation of VP-hPXR, hPXR (previously known as (CAR) were originally identified as sensors able to respond to numer- VPSXR and SXR) transgenic mice and PXR null mice has been ous environmentally derived foreign compounds (xenobiotics) to described (8). promote detoxification by phase I cytochrome P450 genes. In this report, we show that both receptors can induce specific UGT1A UGT1A1 Promoter Cloning and Site-Directed Mutagenesis.
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