title: Resveratrol effectively attenuates α-naphthyl-isothiocyanate-induced acute cholestasis and liver injury through choleretic and anti-inflammatory mechanisms.
abstract: OBJECTIVE
  α-Naphthylisothiocyanate (ANIT) is a well-characterized cholestatic agent for rats. The aim of this study was to examine whether resveratrol could attenuate ANIT-induced acute cholestasis and liver injury in rats.
  
  
  METHODS
  SD rats were treated with resveratrol (15 or 30 mg/kg, ip) or a positive control drug ursodeoxycholic acid (100 mg/kg, po) for 5 consecutive days followed by a single dose of ANIT (60 mg/kg, po). Bile flow, and serum biochemical markers and bile constituents were measured 48 h after ANIT administration. Hepatic levels of oxidative repair enzymes (glutathione peroxidase, catalase and MnSOD), myeloperoxidase activity, TNF-α, IL-6 and ATP content, as well as the expression of liver transporter genes and proteins were assayed.
  
  
  RESULTS
  ANIT exposure resulted in serious cholestasis and liver injury, as shown by marked neutrophil infiltration in liver, dramatically increased serum levels of ALT, AST, GGT, ALP, TBA, TBIL, IBIL and DBIL, and significantly decreased bile excretion and biliary output of GSH and HCO3(-). ANIT significantly increased TNF-α and IL-6 release and myeloperoxidase activity, decreased mitochondrial biogenesis in liver, but had little effect on hepatic oxidative repair enzymes and ATP content. Furthermore, ANIT significantly decreased the expression of Mrp2, FXR and Cyp7a1, markedly increased Mrp3 expression in liver. Pretreatment with resveratrol attenuated ANIT-induced acute cholestasis and liver injury, and other pathological changes. Pretreatment with ursodeoxycholic acid was less effective.
  
  
  CONCLUSIONS
  Resveratrol effectively attenuates ANIT-induced acute cholestasis and liver injury in rats, possibly through suppression of neutrophil infiltration, as well as upregulation of expression of hepatic transporters and enzymes, thus decreasing accumulation of bile acids.
authors.affiliation: 1] Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China [2] Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
authors.forename: Zhi-xing
authors.initials: ZX
authors.lastname: Zhou
authors.affiliation: Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Li-xin
authors.initials: LX
authors.lastname: Sun
authors.affiliation: Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Zhi-meng
authors.initials: ZM
authors.lastname: Xu
authors.affiliation: Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Mi
authors.initials: M
authors.lastname: Chen
authors.affiliation: Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Guo-lin
authors.initials: GL
authors.lastname: Zhao
authors.affiliation: 1] Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China [2] Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Zhen-zhou
authors.initials: ZZ
authors.lastname: Jiang
authors.affiliation: 1] Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China [2] State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Lu-yong
authors.initials: LY
authors.lastname: Zhang
mesh_terms: D015058:1-Naphthylisothiocyanate; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001646:Bile / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D002779:Cholestasis / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D019610:Cytoprotection; D004272:DNA, Mitochondrial / Q000378:metabolism; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D002756:Cholagogues and Choleretics; D004272:DNA, Mitochondrial; D018836:Inflammation Mediators; D026901:Membrane Transport Proteins; D013267:Stilbenes; D015058:1-Naphthylisothiocyanate; D000255:Adenosine Triphosphate; D000077185:Resveratrol