Journal Article

Loss of A<sub>1</sub> Adenosine Receptor Attenuates Alpha-naphthylisothiocyanate-Induced Cholestatic Liver Injury in Mice

Ping Yang, Peng Chen, Tao Wang, Yibei Zhan, Mengyi Zhou, Lin Xia, Rui Cheng, Yating Guo, Lin Zhu and Jianfa Zhang

in Toxicological Sciences

Volume 131, issue 1, pages 128-138
Published in print January 2013 | ISSN: 1096-6080
Published online September 2012 | e-ISSN: 1096-0929 | DOI:
Loss of A1 Adenosine Receptor Attenuates Alpha-naphthylisothiocyanate-Induced Cholestatic Liver Injury in Mice

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Cholestasis has limited therapeutic options and is associated with high morbidity and mortality. The A1 adenosine receptor (A 1 AR) was postulated to participate in the pathogenesis of hepatic fibrosis induced by experimental extrahepatic cholestasis; however, the contribution of A 1 AR to intrahepatic cholestatic liver injury remains unknown. Here, we found that mice lacking A 1 AR were resistant to alpha-naphthyl isothiocyanate (ANIT)–induced liver injury, as evidenced by lower serum liver enzyme levels and reduced extent of histological necrosis. Bile acid accumulation in liver and serum was markedly diminished in A 1 AR −/− mice compared with wild-type (WT) mice. However, biliary and urinary outputs of bile acids were significantly enhanced in A 1 AR −/− mice. In the liver, mRNA expression of genes related to bile acid transport (Bsep and Mdr2) and hydroxylation (Cyp3a11) was increased in A 1 AR −/− mice. In the kidney, A 1 AR deficiency prevented the decrease of glomerular filtration rate caused by ANIT. Treatment of WT mice with A1AR antagonist DPCPX also protected against ANIT hepatotoxicity. Our results indicated that lack of A 1 AR gene protects mice from ANIT-induced cholestasis by enhancing toxic biliary constituents efflux through biliary excretory route and renal elimination system and suggested a potential role of A 1 AR as therapeutic target for the treatment of intrahepatic cholestasis.

Keywords: A1AR; ANIT; cholestasis; bile acid; DPCPX

Journal Article.  6405 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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