title: The heat shock protein 90 inhibitor, 17-AAG, attenuates thioacetamide induced liver fibrosis in mice.
abstract: BACKGROUND
  Heat shock protein 90 (Hsp90) is proposed to be involved in liver disorders. This study was conducted to test effect of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of Hsp90, on attenuating thioacetamide induced liver fibrosis in vivo.
  
  
  METHODS
  Four groups of Swiss albino male mice (CD-1 strain) were used as follows: control group; thioacetamide group (received 100mg/kg thioacetamide, ip injection, 3 times/week for 8 weeks); thioacetamide plus 17-AAG groups (received 100mg/kg thioacetamide, ip injection, 3 times/week for 8 weeks plus 25 or 50mg/kg 17-AAG, ip injection, 5 days/week along the last 4 weeks). Fibrosis was quantified by measuring hydroxyproline level and by morphometry and oxidative stress biomarkers were assigned. Relative hepatic mRNA expressions of α-smooth muscle actin (α-SMA), collagen-1-alpha-1 (Col1A1) and tissue inhibitor metalloproteinase-1 (TIMP-1) mRNAs were measured by RT-PCR. Levels of the apoptotic markers caspase-3, factor related apoptosis (Fas) and Hsp-90 were assigned in tissue homogenate.
  
  
  RESULTS
  17-AAG (50mg/kg) significantly decreased fibrosis percentage significantly (p<0.001, 0.05) compared to thioaceatmide and 25mg/kg, respectively. Malondialdehyde, Hsp90, α-SMA, Col1A1 and TIMP-1 expression levels were significantly reduced (p<0.05) by the inhibitor large dose. Levels of GSH, caspase-3 and Fas were markedly (p<0.001) increased in the group received 17-AAG (50mg/kg) compared to other groups.
  
  
  CONCLUSIONS
  The Hsp90 inhibitor, 17-AAG, can attenuate thioacetamide hepatotoxicity through oxidative stress counterbalance, reducing stellate cells activity and inducing apoptosis.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. Electronic address: nosha.samaa@gmail.com.
authors.forename: Nashwa M
authors.initials: NM
authors.lastname: Abu-Elsaad
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. Electronic address: marwa.sereya@hotmail.com.
authors.forename: Marwa S
authors.initials: MS
authors.lastname: Serrya
authors.affiliation: Department of Pathology and Toxicology, Faculty of Medicine, Mansoura University, Mansoura, Egypt. Electronic address: aelkaref@yahoo.com.
authors.forename: Amr M
authors.initials: AM
authors.lastname: El-Karef
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. Electronic address: tarekmoss@yahoo.com.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Ibrahim
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D005978:Glutathione / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000188:drug therapy*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D013853:Thioacetamide / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000199:Actins; D016227:Benzoquinones; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D019715:Tissue Inhibitor of Metalloproteinase-1; C544013:alpha-smooth muscle actin, mouse; D019014:fas Receptor; D013853:Thioacetamide; C112765:tanespimycin; D008315:Malondialdehyde; D053148:Caspase 3; D005978:Glutathione
keywords: 17-AAG; Apoptosis; Heat shock protein; Liver fibrosis