TY - JOUR T1 - Effects of Alterations in CAR on Bilirubin Detoxification in Mouse Collagen-Induced Arthritis JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 256 LP - 261 DO - 10.1124/dmd.106.011536 VL - 35 IS - 2 AU - Atsushi Kawase AU - You Tsunokuni AU - Masahiro Iwaki Y1 - 2007/02/01 UR - http://dmd.aspetjournals.org/content/35/2/256.abstract N2 - Nuclear receptors such as constitutive androstane receptor (CAR) and pregnane X receptor (PXR) regulate the transcription of cytochromes P450 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 with 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-glucuronosyl-transferase 1A1, and multidrug resistance-associated protein 2 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 because of changes in multiple bilirubin-detoxifying enzymes and transporters. The American Society for Pharmacology and Experimental Therapeutics ER -