The role of hepatocyte RXR alpha in xenobiotic-sensing nuclear receptor-mediated pathways.
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 alpha (RXRalpha) dimerizes with CAR and PXR. In order to analyze the role of RXRalpha in these xeno-sensor-mediated pathways, hepatocyte RXRalpha-deficient mice were challenged by CAR and PXR ligands including androstanol, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), and pregnenolone 16alpha-carbonitrile (PCN). We demonstrate that hepatocyte RXRalpha 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 RXRalpha target genes. Androstanol, TCPOBOP, and PCN can differentially regulate the expression of these CYP450 genes. In addition, the most active peroxisome proliferator activated receptor (PPARalpha) 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 RXRalpha is essential for xenobiotic metabolism in vivo.
Cai
Yan
Y
Department of Pathology, Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90509, USA.
Konishi
Tamiko
T
Han
Guang
G
Campwala
Khozema H
KH
French
Samuel W
SW
Wan
Yu-Jui Yvonne
YJ
D000732:Androstanols / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006529:Hepatomegaly / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D047488:Retinoid X Receptors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013250:Steroid Hydroxylases; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015262:Xenobiotics / Q000378:metabolism*
D000732:Androstanols; D011725:Pyridines; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D015262:Xenobiotics; C000658:androstan-3-ol; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; C006253:pirinixic acid; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; D000072467:Cytochrome P450 Family 2