title: Effects of dietary iron overload on progression in chemical hepatocarcinogenesis.
abstract: OBJECTIVE
  The present study was undertaken to investigate possible effects of dietary iron during the progression step in hepatocarcinogenesis.
  
  
  METHODS
  Two experiments were performed, in which preneoplastic foci were produced in rat liver using the Solt & Farber protocol, with diethylnitrosamine as initiator and partial hepatectomy + 2-acetylaminofluorene as promoter. Two weeks after promotion, animals were fed 1.25-2.5% dietary carbonyl iron or a control diet until sacrifice. In the first experiment, animals were killed at different time points when they developed an abdominal mass in combination with weight loss. In the second experiment, animals were sacrificed 45 weeks post-promotion. Liver tumours were counted and histologically graded. Tumour levels of ubiquinone-9 and alpha-tocopherol were determined with HPLC, and labelling and apoptotic indices calculated using immunohistochemistry. The number and area of glutathione S-transferase 7,7 (GST-7,7)-positive foci were determined.
  
  
  RESULTS
  In experiment number 1, survival and tumour differentiation were similar in iron-treated animals and controls. In the second experiment, iron-treated rats had an increased number of GST-7,7-positive foci compared to controls. Number and size of carcinomas were similar between the groups, whereas tumour differentiation was higher in rats exposed to iron. Cell proliferation, apoptosis and concentrations of alpha-tocopherol in tumours were not altered by iron. The ratio of reduced/oxidized ubiquinone-9 was decreased in tumours from iron-treated animals.
  
  
  CONCLUSIONS
  In this model, dietary iron overload resulted in an increased number of preneoplastic foci but did not enhance the progression of these into hepatocellular carcinomas. Iron decreased the ratio of reduced/oxidized ubiquinone-9 in tumours, indicating that neoplastic liver cells utilize intracellular ubiquinones as a defense mechanism against iron-induced oxidative stress.
authors.affiliation: Department of Gastroenterology and Hepatology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Stål
authors.forename: G S
authors.initials: GS
authors.lastname: Wang
authors.forename: J M
authors.initials: JM
authors.lastname: Olsson
authors.forename: L C
authors.initials: LC
authors.lastname: Eriksson
mesh_terms: D015073:2-Acetylaminofluorene; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004052:Diethylnitrosamine; D018450:Disease Progression; D005982:Glutathione Transferase / Q000378:metabolism; D006432:Hemochromatosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D007501:Iron / Q000378:metabolism; D019266:Iron, Dietary / Q000008:administration & dosage*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014451:Ubiquinone / Q000378:metabolism; D014810:Vitamin E / Q000378:metabolism
chemical_list: D002273:Carcinogens; D019266:Iron, Dietary; D014451:Ubiquinone; D014810:Vitamin E; D004052:Diethylnitrosamine; D015073:2-Acetylaminofluorene; D007501:Iron; D005982:Glutathione Transferase; C030571:ubiquinone 9