Title: INDUCTION OF BILIRUBIN CLEARANCE BY THE CONSTITUTIVE ANDROSTANE RECEPTOR (CAR) Authors
|Huang, Wendong - BAYLOR COLL MED|
|Zhang, Jun - BAYLOR COLL MED|
|Chua, Steven - BAYLOR COLL MED|
|Qatanani, Mohammed - BAYLOR COLL MED|
|Han, Yunqing - BAYLOR COLL MED|
|Granata, Riccarda - UNIV TURIN-MOLINETTE HOSP|
Submitted to: Proceedings of the National Academy of Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 23, 2002
Publication Date: April 1, 2003
Citation: Huang, W., Zhang, J., Chua, S.S., Qatanani, M., Han, Y., Granata, R., Moore, D.D. 2003. Induction of bilirubin clearance by the constitutive androstane receptor (CAR). Proceedings of the National Academy of Science. 100(7):4156-4161. Interpretive Summary: Bilirubin clearance is one of the numerous important functions of the liver. Defects in this process result in jaundice, which is particularly common in neonates. Elevated bilirubin levels can be decreased by treatment with phenobarbital. This study compared the bilirubin clearance rates of normal mice and mice that lacked the hormone receptor constitutive androstane receptor (CAR). In normal mice, but not those lacking CAR, activation of the CAR increases clearance of bilirubin. We also found that CAR expression is low in neonatal mice and humans. This functional deficit may contribute to neonatal jaundice.
Technical Abstract: Bilirubin clearance is one of the numerous important functions of the liver. Defects in this process result in jaundice, which is particularly common in neonates. Elevated bilirubin levels can be decreased by treatment with phenobarbital. Because the nuclear hormone receptor constitutive androstane receptor (CAR) mediates hepatic effects of this xenobiotic inducer, we hypothesized that CAR could be a regulator of bilirubin clearance. Activation of the nuclear hormone receptor CAR increases hepatic expression of each of five components of the bilirubin-clearance pathway. This induction is absent in homozygous CAR null mice but is observed in mice expressing human CAR instead of mouse CAR. Pretreatment with xenobiotic inducers markedly increases the rate of clearance of an exogenous bilirubin load in wild-type but not CAR knockout animals. Bilirubin itself can also activate CAR, and mice lacking CAR are defective in clearing chronically elevated bilirubin levels. Unexpectedly, CAR expression is very low in livers of neonatal mice and humans. We conclude that CAR directs a protective response to elevated bilirubin levels and suggest that a functional deficit of CAR activity may contribute to neonatal jaundice.