Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor

Abstract

Through a multiplex promoter spanning 218 kb, the phase II UDPglucuronosyltransferase 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.

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

“…Both receptors protect the body from the deleterious accumulation of bilirubin [61,62] and bile acids [63] through hepatic induction of several enzyme genes. Additionally, many CAR and PXR target genes, including CYP3A and CYP2B, are involved in steroid hormone metabolism and their induction could contribute to the endocrine disruption activities of drugs and contaminants [64,65].…”

Identification of novel androgen response genes in prostate cancer cells by coupling chromatin immunoprecipitation and genomic microarray analysis

“…UGT1A gene products are generated by a strategy of exon sharing, resulting in divergent isoforms with a unique N-terminal domain and commonly shared C-terminal 245 amino acids. As UGT proteins are detoxifying enzymes, it is natural that this gene expression is regulated by xenobiotic receptor including pregnenolone X receptor and constitutive androstane receptor (Sugatani et al, 2001;Xie et al, 2003). Reduction of UGT1A expression is involved in the early phase of neoplastic transformation, such as in liver and biliary cancer, bladder cancer and colon cancer (Strassburg et al, 1997;Giuliani et al, 2005).…”

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

“…In support of the role of these LATFs in bilirubin catabolism, 10 phenobarbital-type inducers in human primary hepatocyte cultures [79]. Bilirubin clearance is also enhanced by activators of PXR [80]. Hence, bilirubin-activated LATFs may provide an autoregulatory feedback loop which is not only operative in the stressful perinatal period but also in the adult.…”