Abstract
Nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) cross talk and serve as xenobiotic sensors to form a safety net against the toxic effects of harmful substances. Retinoid x receptor α (RXRα) dimerizes with CAR and PXR. In order to analyze the role of RXRα in these xeno-sensor-mediated pathways, hepatocyte RXRα-deficient mice were challenged by CAR and PXR ligands including androstanol, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), and pregnenolone 16α-carbonitrile (PCN). We demonstrate that hepatocyte RXRα deficiency prevents TCPOBOP-induced hepatomegaly and morphological changes. We also show that in vivo the cytochrome P450 (CYP) genes including CYP2A5, CYP2B10, CYP3A1, but not CYP2E1 and CYP2D6, are the RXRα target genes. Androstanol, TCPOBOP, and PCN can differentially regulate the expression of these CYP450 genes. In addition, the most active peroxisome proliferator activated receptor (PPARα) ligand, Wy14,643, also regulates some of the xeno-sensor target genes such as CYP2A5 and CYP2B10 in vivo. Thus, the ligands of different nuclear receptors can regulate common CYP450 genes and hepatocyte RXRα is essential for xenobiotic metabolism in vivo.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 89-96 |
| Number of pages | 8 |
| Journal | European Journal of Pharmaceutical Sciences |
| Volume | 15 |
| Issue number | 1 |
| DOIs | |
| State | Published - 2002 |
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Keywords
- Constitutive androstane receptor
- CYP450
- Nulcear receptor
- Peroxisome proliferator activated receptor
- Pregnane X receptor
- Retinoid x receptor
- Xenobiotic
ASJC Scopus subject areas
- Pharmaceutical Science
Cite this
The role of hepatocyte RXRα in xenobiotic-sensing nuclear receptor-mediated pathways. / Cai, Yan; Konishi, Tamiko; Han, Guang; Campwala, Khozema H.; French, Samuel W.; Wan, Yu-Jui Yvonne.
In: European Journal of Pharmaceutical Sciences, Vol. 15, No. 1, 2002, p. 89-96.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The role of hepatocyte RXRα in xenobiotic-sensing nuclear receptor-mediated pathways
AU - Cai, Yan
AU - Konishi, Tamiko
AU - Han, Guang
AU - Campwala, Khozema H.
AU - French, Samuel W.
AU - Wan, Yu-Jui Yvonne
PY - 2002
Y1 - 2002
N2 - Nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) cross talk and serve as xenobiotic sensors to form a safety net against the toxic effects of harmful substances. Retinoid x receptor α (RXRα) dimerizes with CAR and PXR. In order to analyze the role of RXRα in these xeno-sensor-mediated pathways, hepatocyte RXRα-deficient mice were challenged by CAR and PXR ligands including androstanol, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), and pregnenolone 16α-carbonitrile (PCN). We demonstrate that hepatocyte RXRα deficiency prevents TCPOBOP-induced hepatomegaly and morphological changes. We also show that in vivo the cytochrome P450 (CYP) genes including CYP2A5, CYP2B10, CYP3A1, but not CYP2E1 and CYP2D6, are the RXRα target genes. Androstanol, TCPOBOP, and PCN can differentially regulate the expression of these CYP450 genes. In addition, the most active peroxisome proliferator activated receptor (PPARα) ligand, Wy14,643, also regulates some of the xeno-sensor target genes such as CYP2A5 and CYP2B10 in vivo. Thus, the ligands of different nuclear receptors can regulate common CYP450 genes and hepatocyte RXRα is essential for xenobiotic metabolism in vivo.
AB - Nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) cross talk and serve as xenobiotic sensors to form a safety net against the toxic effects of harmful substances. Retinoid x receptor α (RXRα) dimerizes with CAR and PXR. In order to analyze the role of RXRα in these xeno-sensor-mediated pathways, hepatocyte RXRα-deficient mice were challenged by CAR and PXR ligands including androstanol, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), and pregnenolone 16α-carbonitrile (PCN). We demonstrate that hepatocyte RXRα deficiency prevents TCPOBOP-induced hepatomegaly and morphological changes. We also show that in vivo the cytochrome P450 (CYP) genes including CYP2A5, CYP2B10, CYP3A1, but not CYP2E1 and CYP2D6, are the RXRα target genes. Androstanol, TCPOBOP, and PCN can differentially regulate the expression of these CYP450 genes. In addition, the most active peroxisome proliferator activated receptor (PPARα) ligand, Wy14,643, also regulates some of the xeno-sensor target genes such as CYP2A5 and CYP2B10 in vivo. Thus, the ligands of different nuclear receptors can regulate common CYP450 genes and hepatocyte RXRα is essential for xenobiotic metabolism in vivo.
KW - Constitutive androstane receptor
KW - CYP450
KW - Nulcear receptor
KW - Peroxisome proliferator activated receptor
KW - Pregnane X receptor
KW - Retinoid x receptor
KW - Xenobiotic
UR - http://www.scopus.com/inward/record.url?scp=0036170810&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036170810&partnerID=8YFLogxK
U2 - 10.1016/S0928-0987(01)00211-1
DO - 10.1016/S0928-0987(01)00211-1
M3 - Article
C2 - 11803135
AN - SCOPUS:0036170810
VL - 15
SP - 89
EP - 96
JO - European Journal of Pharmaceutical Sciences
JF - European Journal of Pharmaceutical Sciences
SN - 0928-0987
IS - 1
ER -