Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor.
Through a multiplex promoter spanning 218 kb, the phase II UDP-glucuronosyltransferase 1A (UGT1) gene encodes at least eight differently regulated mRNAs whose protein products function as the principal means to eliminate a vast array of steroids, heme metabolites, environmental toxins, and drugs. The orphan nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) were originally identified as sensors able to respond to numerous environmentally derived foreign compounds (xenobiotics) to promote detoxification by phase I cytochrome P450 genes. In this report, we show that both receptors can induce specific UGT1A isoforms including those involved in estrogen, thyroxin, bilirubin, and carcinogen metabolism. Transgenic mice expressing a constitutively active form of human PXR show markedly increased UGT activity toward steroid, heme, and carcinogens, enhanced bilirubin clearance, as well as massively increased steroid clearance. The ability of PXR and constitutive androstane receptor and their ligands to transduce both the phase I and phase II adaptive hepatic response defines a unique transcriptional interface that bridges the ingestion and metabolism of environmental compounds to body physiology.
Xie
Wen
W
Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Yeuh
Mei-Fei
MF
Radominska-Pandya
Anna
A
Saini
Simrat P S
SP
Negishi
Yoichi
Y
Bottroff
Bobbie Sue
BS
Cabrera
Geraldine Y
GY
Tukey
Robert H
RH
Evans
Ronald M
RM
D000818:Animals; D001483:Base Sequence; D001663:Bilirubin / Q000378:metabolism; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D000090702:Constitutive Androstane Receptor; D017931:DNA Primers; D005091:Exons; D005786:Gene Expression Regulation / Q000502:physiology; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013256:Steroids / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D000099148:UGT1A1 Enzyme
D001663:Bilirubin; D002273:Carcinogens; D000090702:Constitutive Androstane Receptor; D017931:DNA Primers; D014453:Glucuronosyltransferase; D006418:Heme; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011994:Recombinant Proteins; D013256:Steroids; D014157:Transcription Factors; D000099148:UGT1A1 Enzyme