title: The flavonoid monoHER prevents monocrotaline-induced hepatic sinusoidal injury in rats.
abstract: BACKGROUND
  Sinusoidal obstruction syndrome (SOS) occurs in 50-70% of patients after oxaliplatin treatment for hepatic colorectal metastasis. SOS is associated with portal hypertension and is caused by oxidative damage to endothelial cells and matrix metalloproteinase (MMP) induction. We studied the effect of a flavonoid (monoHER) on SOS prevention.
  
  
  METHODS
  A monocrotaline (MTC) SOS model was used in rats, with pre-treatment of monoHER. We studied hepatocellular damage and MMP expression. The potential inhibition of oxaliplatin cytotoxicity by monoHER was tested in vitro in colorectal cancer cell lines.
  
  
  RESULTS
  MonoHER ameliorated the increase in portal pressure after MCT (72 hr: 7.3 ± 2.7 mmHg vs. 11.4 ± 3.0 mmHg, P = 0.016 MCT + monoHER vs. MCT, P < 0.01). MonoHER prevented hepatocellular damage (ALT: 48 hr 42.2 ± 3.1 IU/L vs. 253.4 ± 171.7 IU/L, P = 0.034; 72 hr: 46.2 ± 4.3 IU/L vs. 311.9 ± 163.6 IU/L, MCT + monoHER vs. MCT, P < 0.01). The liver damage score was lower in the monoHER group (72 hr: 4.8 ± 3.6 vs. 10.3 ± 0.5, MCT-monoHER vs. MCT, P < 0.01) associated with less inflammatory cell infiltration. Livers of MCT treated rats had higher expression of MMP-9 when compared to monoHER pairs at 24 hr (P = 0.016) and 72 hr (P < 0.001). MonoHER had no effect on in vitro proliferation of colorectal cancer cells when used either alone or in combination with oxaliplatin.
  
  
  CONCLUSIONS
  MonoHER prevented MCT induced portal hypertension and hepatic injury in rats.
authors.affiliation: UCL Hepatology, Department of HPB and Liver Transplantation Surgery, University College London Medical School, Royal Free Campus, London, UK.
authors.forename: Tarek
authors.initials: T
authors.lastname: Ezzat
authors.forename: Maartje A J
authors.initials: MA
authors.lastname: van den Broek
authors.forename: Nathan
authors.initials: N
authors.lastname: Davies
authors.forename: Cornelis H C
authors.initials: CH
authors.lastname: Dejong
authors.forename: Aalt
authors.initials: A
authors.lastname: Bast
authors.forename: Massimo
authors.initials: M
authors.lastname: Malagó
authors.forename: Dipok K
authors.initials: DK
authors.lastname: Dhar
authors.forename: Steven W M
authors.initials: SW
authors.lastname: Olde Damink
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D006896:Hydroxyethylrutoside / Q000031:analogs & derivatives* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D016686:Monocrotaline; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D000077150:Oxaliplatin; D018384:Oxidative Stress / Q000187:drug effects; D017082:Portal Pressure / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C522803:7-monohydroxyethylrutoside; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D006896:Hydroxyethylrutoside; D009944:Organoplatinum Compounds; D020011:Protective Agents; D000077150:Oxaliplatin; D016686:Monocrotaline; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9