title: Effect of JBP485 on obstructive jaundice is related to regulation of renal Oat1, Oat3 and Mrp2 expression in ANIT-treated rats.
abstract: The objective was to determine whether protective effects of JBP485 on biliary obstruction induced by alpha-naphthylisothiocyanate (ANIT) are mediated by the organic anion transporters Oat1, Oat3 and the multidrug resistance-associated protein Mrp2. The ANIT-induced increases in bilirubin (BIL), alanine aminotransferase (ALT) and aspartate transaminase (AST) in rat serum were inhibited significantly by oral administration of JBP485. The plasma concentration of JBP485 which is the substrate of Oat1 and Oat3 determined by LC-MS/MS was markedly increased after intravenous administration in ANIT-treated rats, whereas cumulative urinary excretion of JBP485 in vivo and the uptake of JBP485 in kidney slices were decreased remarkably. RT-PCR and Western blot showed the decreased expression of Oat1 and Oat3, increased expression of Mrp2 in ANIT-induced rats, meanwhile, the expression levels of Mrp2 and Oat1 were up-regulated after administration of JBP485. The up-regulation of Mrp2 and Oat1 was associated with a concomitant increase in urinary BIL after treatment with JBP485 in ANIT-treated rats. The mechanism for JBP485 to restore liver function might be related to improvement of the expression and function for Oat1 and Mrp2 as well as facilitation of urinary excretion for hepatoxic substance.
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. liutaomedical@qq.com
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Xinjin
authors.initials: X
authors.lastname: Guo
authors.forename: Qiang
authors.initials: Q
authors.lastname: Meng
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Huijun
authors.initials: H
authors.lastname: Sun
authors.forename: Xiaochi
authors.initials: X
authors.lastname: Ma
authors.forename: Taiichi
authors.initials: T
authors.lastname: Kaku
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
mesh_terms: D015058:1-Naphthylisothiocyanate; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood / Q000652:urine; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D041781:Jaundice, Obstructive / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D014158:Transcription, Genetic
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; C412308:JBP 485; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D010456:Peptides, Cyclic; C421043:Slc22a6 protein, rat; C114338:organic anion transport protein 3; D015058:1-Naphthylisothiocyanate; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001663:Bilirubin