title: Deleterious effects of silymarin on the expression of genes controlling endothelial nitric oxide synthase activity in carbon tetrachloride-treated rat livers.
abstract: OBJECTIVE
  Defects in intrahepatic nitric oxide (NO) are attributed to reduced blood flow due to portal hypertension caused by diminished endothelial NO synthase (eNOS) activity. The aim of this study is to identify the therapeutic effects of silymarin on eNOS/NO-related enzymes and hepatic enzymes in carbon tetrachloride (CCl4)-induced cirrhotic rats.
  
  
  METHODS
  CCl4 treated for 12 weeks was discontinued and then administrated with silymarin daily for 4 weeks. Collagen concentrations were determined by measuring hydroxyproline content. Serum was assayed for hepatic enzymes like alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities. NOS activities were measured by oxyhemoglobin oxidation assay, and levels of enzyme expression and phosphorylation were detected by Western-blot analyses.
  
  
  RESULTS
  Silymarin treatment restored the values for collagen content and ALT and ALP activities when compared to the values with spontaneous resolution following discontinuation of CCl4. CCl4 treatment highly increased eNOS expression and NOS activity in livers, but the phosphorylation was markedly decreased. Silymarin decreased significantly eNOS expression and activity. Expression and/or phosphorylation of enzymes activating eNOS were unchanged (Akt and AMPK) or decreased (PKA) by silymarin. Especially, the expression of caveolin-1, an inhibitor of eNOS was unchanged by CCl4, but its phosphorylation was significantly increased. However, silymarin markedly increased caveolin-1 expression but decreased its phosphorylation to expression.
  
  
  CONCLUSIONS
  These results suggest that chronic silymarin treatment can improve cirrhosis-induced liver enzyme activities and fibrosis, but may aggravate the hemodynamic eNOS activity, particularly by decreasing eNOS expression and increasing caveolin-1 expression.
authors.affiliation: Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 110-746, Republic of Korea.
authors.forename: Yong Kyun
authors.initials: YK
authors.lastname: Cho
authors.forename: Jung Won
authors.initials: JW
authors.lastname: Yun
authors.forename: Jung Ho
authors.initials: JH
authors.lastname: Park
authors.forename: Hong Joo
authors.initials: HJ
authors.lastname: Kim
authors.forename: Dong Il
authors.initials: DI
authors.lastname: Park
authors.forename: Chong Il
authors.initials: CI
authors.lastname: Sohn
authors.forename: Woo Kyu
authors.initials: WK
authors.lastname: Jeon
authors.forename: Byung Ik
authors.initials: BI
authors.lastname: Kim
authors.forename: Wook
authors.initials: W
authors.lastname: Jin
authors.forename: Yong-Hyun
authors.initials: YH
authors.lastname: Kwon
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Shin
authors.forename: Tae Moo
authors.initials: TM
authors.lastname: Yoo
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
authors.forename: Chang-Shin
authors.initials: CS
authors.lastname: Park
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002251:Carbon Tetrachloride; D003094:Collagen / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D008111:Liver Function Tests; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D020011:Protective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012838:Silymarin / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D020011:Protective Agents; D012838:Silymarin; D003094:Collagen; D002251:Carbon Tetrachloride; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat