Modulation of organic anion transporting polypeptide 1 and multidrug resistance protein 3 expression in the liver and kidney of Gunn rats.
Background: Gunn rat is an animal model of Crigler-Najjar syndrome (CNS) type I that develops jaundice due to defect of bilirubin conjugation. Bilirubin UDP-glucuronosyltransferase (UGT1A1), which plays a critical role in bilirubin glucuronidation, has been reported to be deficient in CNS type 1. On the other hand, little is known about the expression of organic anion transporters in Gunn rats. In the present study, we evaluated expressions of organic anion transporting polypeptide (oatp) 1 and 2, multidrug resistance-associated protein (mrp) 2 and mrp3 in the liver and kidney of Gunn rats. Methods: Serum samples, liver and kidney tissues were obtained from Gunn rats and normal SD rats ( [Formula: see text], in each group). Semi-quantitative mRNA expression of oatp1, oatp2, mrp2, and mrp3 mRNA was evaluated by constructed reverse transcription-polymerase chain reaction (RT-PCR). Protein expressions were determined by Western blotting and by immunohistochemistry. Results: Marked elevation of serum unconjugated bilirubin concentration ( [Formula: see text] micromol/l) was observed in Gunn rats. Hepatic expression of oatp1 and oatp2 mRNA was 44% ( [Formula: see text] ) and 35% ( [Formula: see text] ) lower in Gunn rats than in SD rats, respectively. Hepatic oatp1 protein expression was 37% ( [Formula: see text] ) lower in Gunn rats than in SD rats. In contrast to oatp1, hepatic expression of mrp3 mRNA and protein was 76% ( [Formula: see text] ) and 557% ( [Formula: see text] ) higher in Gunn rats than in SD rats, respectively. Hepatic expression of oatp2 and mrp2 protein was not significantly different between Gunn rats and SD rats. Like the Western blot analysis, immunohistochemical staining disclosed decrease of oatp1 and increase of mrp3 protein expressions in the liver of Gunn rats. Decrease of oatp1 and increase of mrp3 expressions were also observed in the kidney of Gunn rats. Conclusion: Decreased expression of oatp1 and increased expression of mrp3 were observed in the liver and kidney of Gunn rats. Deficient UGT1A1 activity-associated retention of unconjugated bilirubin in the hepatocytes may modulate the expressions of these transporters in Gunn rats.
Higuchi
Kunihiro
K
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
Kobayashi
Yoshinao
Y
Kuroda
Makoto
M
Tanaka
Yuji
Y
Itani
Toshio
T
Araki
Jun
J
Mifuji
Rumi
R
Kaito
Masahiko
M
Adachi
Yukihiko
Y