Loss of A1 Adenosine Receptor Attenuates Alpha-naphthylisothiocyanate-Induced Cholestatic Liver Injury in Mice.

Cholestasis has limited therapeutic options and is associated with high morbidity and mortality. The A1 adenosine receptor (A1AR) was postulated to participate in the pathogenesis of hepatic fibrosis induced by experimental extrahepatic cholestasis; however, the contribution of A1AR to intrahepatic cholestatic liver injury remains unknown. Here, we found that mice lacking A1AR 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 A1AR−/− mice compared with wild-type (WT) mice. However, biliary and urinary outputs of bile acids were significantly enhanced in A1AR−/− mice. In the liver, mRNA expression of genes related to bile acid transport (Bsep and Mdr2) and hydroxylation (Cyp3a11) was increased in A1AR−/− mice. In the kidney, A1AR 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 A1AR 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 A1AR as therapeutic target for the treatment of intrahepatic cholestasis. [ABSTRACT FROM PUBLISHER]