Effect of oncostatin M on uridine diphosphate-5'-glucuronosyltransferase 1A1 through cross talk with constitutive androstane receptor

Hisashi Masuyama; Hideki Nakatsukasa; Yuji Hiramatsu

doi:10.1210/me.2009-0478

Effect of oncostatin M on uridine diphosphate-5'-glucuronosyltransferase 1A1 through cross talk with constitutive androstane receptor

Mol Endocrinol. 2010 Apr;24(4):745-53. doi: 10.1210/me.2009-0478. Epub 2010 Mar 2.

Authors

Hisashi Masuyama¹, Hideki Nakatsukasa, Yuji Hiramatsu

Affiliation

¹ Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. masuyama@cc.okayama-u.ac.jp

Abstract

Hyperbilirubinemia remains a common condition in neonates. The constitutive androstane receptor (CAR) is an orphan nuclear receptor that has been shown to participate in the activation of the uridine diphosphate-5'-glucuronosyltransferase 1A1 (UGT1A1) gene, which plays an important role in bilirubin clearance. Oncostatin M (OSM), a member of the IL-6 family, is involved in the maturation of fetal hepatocytes. We have demonstrated that low OSM levels are a potential indicator of neonatal jaundice and the need for phototherapy. In this study we examined the effects of OSM on CAR-mediated signaling to investigate its potential role in neonatal jaundice via the CAR-UGT1A1 pathway. We observed that OSM positively augmented the CAR and UGT1A1 expressions and CAR-mediated signaling in vivo and in vitro, through cross talk between the nuclear CAR receptor and the plasma membrane OSM receptor, via the MAPK cascade. These data suggest that OSM might play a role in bilirubin metabolism via the CAR-UGT1A1 pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Newborn
Blotting, Western
Constitutive Androstane Receptor
Cytochrome P-450 CYP3A / genetics
Cytochrome P-450 CYP3A / metabolism
Flavonoids / pharmacology
Glucuronosyltransferase / genetics
Glucuronosyltransferase / metabolism*
Hep G2 Cells
Humans
Infant, Newborn
Jaundice, Neonatal / metabolism
Mice
Mice, Inbred ICR
Mitogen-Activated Protein Kinases / antagonists & inhibitors
Mitogen-Activated Protein Kinases / metabolism
Oncostatin M / pharmacology*
Oximes / pharmacology
Phenobarbital / pharmacology
Receptors, Cytoplasmic and Nuclear / agonists
Receptors, Cytoplasmic and Nuclear / genetics
Receptors, Cytoplasmic and Nuclear / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / drug effects
Signal Transduction / genetics
Thiazoles / pharmacology

Substances

Constitutive Androstane Receptor
Flavonoids
Oximes
Receptors, Cytoplasmic and Nuclear
Thiazoles
Oncostatin M
6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime
Cytochrome P-450 CYP3A
CYP3A4 protein, human
UGT1A1 enzyme
Glucuronosyltransferase
Mitogen-Activated Protein Kinases
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
Phenobarbital