Received for publication June 16, 2006.
Revised November 14, 2006.
Accepted for publication November 14, 2006.

EFFECTS OF ALTERATIONS IN CAR ON BILIRUBIN DETOXIFICATION IN MOUSE COLLAGEN-INDUCED ARTHRITIS

Abstract

Nuclear receptors such as constitutive androstane receptor (CAR) and pregnane X receptor (PXR) regulate the transcription of cytochrome P450s (CYPs) and transporters. We investigated whether quantitative and functional changes in CAR and PXR could affect bilirubin detoxification in chronic arthritis. The CAR mRNA level was significantly decreased in the liver of mice with collagen-induced arthritis (CIA) compared to control mice. In normal mice treated with CAR agonists, relatively rapid elimination of bilirubin was observed after its intravenous injection. Next, we investigated the effects of CAR on bilirubin-detoxifying enzymes and transporters in arthritis. The mRNA levels of organic anion transporter peptide (OATP) 2, glutathione S-transferase (GST) A1 and GSTA2 were decreased in CIA mice, whereas the mRNA levels of OATP4, UDP-glucuronosyltransferase (UGT) 1A1 and multidrug resistance-associated protein 2 (MRP2) remained unchanged. The protein levels and transport activities of OATP2 were also decreased in CIA mice. Furthermore, the CIA mice actually exhibited retarded elimination of bilirubin after its intravenous injection. These results indicate that alterations to CAR during arthritis affect the elimination of bilirubin due to changes in multiple bilirubin-detoxifying enzymes and transporters.

Key words: CAR, drug disposition, hepatic elimination, hepatic uptake, nuclear receptors, PXR, transporters