1998
DOI: 10.1016/s0092-8674(00)80900-9 View full text |Buy / Rent full text
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Abstract: Steroid hormones exert profound effects on differentiation, development, and homeostasis in higher eukaryotes through interactions with nuclear receptors. We describe a novel orphan nuclear receptor, termed the pregnane X receptor (PXR), that is activated by naturally occurring steroids such as pregnenolone and progesterone, and synthetic glucocorticoids and antiglucocorticoids. PXR exists as two isoforms, PXR.1 and PXR.2, that are differentially activated by steroids. Notably, PXR.1 is efficaciously activated… Show more

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“…We have recently reported that retinoids activate the RXRα/hPXR-mediated pathway and induce endogenous CYP3A4 activity in Huh7 human hepatoma cells [14]. Given that hPXR and VDR share 64% amino acid identity in their ligand binding domain [7], and the networks of hPXR, VDR, and CAR control CYP3A4 gene expression, we anticipated that retinoids may also regulate CYP3A4 gene expression through the RXR/VDR signaling pathway. Using transient transfection assays, real-time PCR for quantification of mRNA levels, enzyme activity assays, gene knockout models, and ChIP assays, we have unequivocally demonstrated that retinoid-activated RXRs/VDR heterodimers and RXRα homodimers, are responsible for the induction of CYP3A4.…”
Section: Discussionmentioning
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“…We have recently reported that retinoids activate the RXRα/hPXR-mediated pathway and induce endogenous CYP3A4 activity in Huh7 human hepatoma cells [14]. Given that hPXR and VDR share 64% amino acid identity in their ligand binding domain [7], and the networks of hPXR, VDR, and CAR control CYP3A4 gene expression, we anticipated that retinoids may also regulate CYP3A4 gene expression through the RXR/VDR signaling pathway. Using transient transfection assays, real-time PCR for quantification of mRNA levels, enzyme activity assays, gene knockout models, and ChIP assays, we have unequivocally demonstrated that retinoid-activated RXRs/VDR heterodimers and RXRα homodimers, are responsible for the induction of CYP3A4.…”
Section: Discussionmentioning
“…It has been well characterized that CYP3A4 gene is regulated by PXR [5][6][7][8], CAR [4], and VDR [9,10]. Induction of Cyp3a11 (homologous of human CYP3A4) mRNA by retinoids in hepatocytes which are deficient in both PXR and CAR would strongly suggest the role of VDR in regulation of Cyp3a11.…”
Section: Retinoids Induce Cyp3a11 Mrna and Increase Cyp3a4 Enzyme Actmentioning
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“…In addition, a hormone response element in the rat Abcc2 promoter (ER-8) was identified, which is bound by heterodimers of the retinoid X receptor α (RXRα, NR2B1 [129]) with the ligand-activated transcription factors farnesoid X receptor (FXR, NR1H4), pregnane X receptor (PXR, NR1I2), or constitutive androstane receptor (CAR, NR1I3) [73]. These nuclear receptors are, for example, activated by bile acids via FXR [132] by various xenobiotics such as the antibiotic rifampicin, the synthetic glucocorticoid dexamethasone, and pregnenolone 16α-carbonitrile via PXR [8, 41,85], or by phenobarbital via CAR [161]. Knowledge of the presence of the hormone response element ER-8 in the rat Abcc2 promoter [73] may now explain studies which describe the induction of Abcc2 mRNA and Abcc2 protein in primary cultures of rat hepatocytes by a number of xenobiotics, including the carcinogen 2-acetylaminofluorene, the anticancer drug cisplatin, the antifungal agent clotrimazole, the antibiotic cycloheximide, dexamethasone, the chemopreventive agents oltipraz and sulforaphane, phenobarbital, and pregnenolone 16α-carbonitrile [23, 73,75,98,137].…”
Section: Transcriptional and Posttranscriptional Regulation Of Abcc2mentioning