title: Studies on genotoxic effects of iron overload and alcohol in an animal model of hepatocarcinogenesis.
abstract: OBJECTIVE
  In order to examine whether iron and alcohol act synergistically during tumor initiation in vivo, we investigated the effects of dietary iron overload and a liquid ethanol-containing diet on the initiation phase of the Solt & Farber model of chemical hepatocarcinogenesis.
  
  
  METHODS
  Following dietary supplementation with carbonyl iron for 8 weeks and ethanol pair-feeding according to Lieber deCarli for 5 weeks, animals were subjected to partial hepatectomy in order to induce regenerative cell proliferation and thereby "fix" putative DNA lesions. Levels of malondialdehyde, reduced and oxidized ubiquinone-9, alpha-tocopherol and 8-oxo-2'-deoxyguanosine were analyzed in liver tissue removed at the time of partial hepatectomy, and blood was collected for determination of alanine amino-transferase activities. Following a 2-week recovery period, promotion was achieved with 0.02% dietary 2-acetylaminofluorene and carbon tetrachloride. Two weeks after the completion of promotion, animals were sacrificed and the number of preneoplastic, glutathione S-transferase 7,7-positive lesions counted. Animals initiated with diethylnitrosamine served as a positive control group.
  
  
  RESULTS
  Serum aminotransferase activities were significantly increased, and hepatic contents of ubiquinol-9 (reduced ubiquinone-9) were significantly decreased in animals exposed to the combination of iron and ethanol in comparison to the other groups. Livers from iron-treated animals had decreased levels of alpha-tocopherol and increased contents of malondialdehyde, whereas treatment with ethanol did not further enhance these alterations. Levels of 8-oxo-2'-deoxyguanosine were not significantly different in animals treated with iron, ethanol or iron + ethanol as compared with controls. The number of preneoplastic foci at the time of sacrifice was not increased in livers exposed to iron and/or ethanol as compared with those from control animals. As expected, the number of foci was significantly increased in positive controls which were initiated with diethylnitrosamine.
  
  
  CONCLUSIONS
  Iron potentiated the cytotoxic effects of ethanol, resulting in increased serum aminotransferase activities and decreased hepatic contents of ubiquinol. However, the combination of iron and ethanol did not exert genotoxic effects detectable as enhanced hepatic levels of 8-oxo-2'-deoxyguanosine, or increased formation of preneoplastic, glutathione S-transferase 7,7-positive lesions in the Solt & Farber model of chemical hepatocarcinogenesis.
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: J
authors.initials: J
authors.lastname: Olsson
authors.forename: P
authors.initials: P
authors.lastname: Svoboda
authors.forename: R
authors.initials: R
authors.lastname: Hultcrantz
authors.forename: M
authors.initials: M
authors.lastname: Harms-Ringdahl
authors.forename: L C
authors.initials: LC
authors.lastname: Eriksson
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity*; D019190:Iron Overload; D008099:Liver / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014451:Ubiquinone / Q000378:metabolism; D014810:Vitamin E / Q000378:metabolism
chemical_list: D000975:Antioxidants; D014451:Ubiquinone; D014810:Vitamin E; D000431:Ethanol; D008315:Malondialdehyde; D000410:Alanine Transaminase; C030571:ubiquinone 9