title: Loss of A(1) adenosine receptor attenuates alpha-naphthylisothiocyanate-induced cholestatic liver injury in mice.
abstract: Cholestasis has limited therapeutic options and is associated with high morbidity and mortality. The A(1) 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 A(1)AR 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.
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing 210094, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Yibei
authors.initials: Y
authors.lastname: Zhan
authors.forename: Mengyi
authors.initials: M
authors.lastname: Zhou
authors.forename: Lin
authors.initials: L
authors.lastname: Xia
authors.forename: Rui
authors.initials: R
authors.lastname: Cheng
authors.forename: Yating
authors.initials: Y
authors.lastname: Guo
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.forename: Jianfa
authors.initials: J
authors.lastname: Zhang
mesh_terms: D015058:1-Naphthylisothiocyanate / Q000633:toxicity*; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000241:Adenosine / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism* / Q000652:urine; D015153:Blotting, Western; D001651:Cholestasis, Extrahepatic / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D005919:Glomerular Filtration Rate; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000502:physiology*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D015058:1-Naphthylisothiocyanate; D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000241:Adenosine; D001647:Bile Acids and Salts; D051544:Cytochrome P-450 CYP3A; D008565:Membrane Proteins; D043682:Receptor, Adenosine A1; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C490549:Abcb11 protein, mouse; C496508:Cyp3a11 protein, mouse