Abstract:
: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.
journal_name
Proc Natl Acad Sci U S Aauthors
Xie W,Yeuh MF,Radominska-Pandya A,Saini SP,Negishi Y,Bottroff BS,Cabrera GY,Tukey RH,Evans RMdoi
10.1073/pnas.0438010100keywords:
subject
Has Abstractpub_date
2003-04-01 00:00:00pages
4150-5issue
7eissn
0027-8424issn
1091-6490pii
0438010100journal_volume
100pub_type
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