The effects of dietary iron on initiation and promotion in chemical hepatocarcinogenesis.
The aim of this study was to evaluate the effects of dietary iron on hepatocarcinogenesis in an animal model mimicking noncirrhotic genetic hemochromatosis. Iron overload may lead to liver cirrhosis and an increased risk of developing primary hepatocellular carcinoma. It is unknown if iron is of pathogenic importance for the carcinogenic process, or whether the increased cancer risk results solely from the cirrhotic process. We investigated the initiating, promoting, and mitogenic properties of carbonyl iron in the Solt-Farber model of chemical hepatocarcinogenesis. A diet supplemented with 2.5% to 3.0% carbonyl iron was either added to, or replaced, the initiating and promoting events in the model. None of the animals developed hepatic fibrosis. Hepatic iron was increased 6- to 13-fold in iron-treated animals, and predominantly located in periportal hepatocytes. Iron as an initiator did not increase the number of glutathione-S-transferase-Yp-positive foci. Iron reduced the number of foci when added to low-dose diethylnitrosamine plus partial hepatectomy, which may be explained by a delayed hepatic regeneration in iron-loaded liver. As a promoter, iron did not selectively induce proliferation of initiated cells. Added to a complete promotive regimen, iron decreased the volume density of preneoplastic nodules, possibly because of a mitostimulatory effect of iron on normal hepatocytes surrounding the nodules. Iron increased the hepatocyte labeling index and counteracted the mitoinhibitory effect of 2-acetylaminofluorene on regenerating liver.(ABSTRACT TRUNCATED AT 250 WORDS)
Stál
P
P
Division of Gastroenterology and Hepatology, Karolinska Institutet, Huddinge University Hospital, Sweden.
Hultcrantz
R
R
Möller
L
L
Eriksson
L C
LC
D015073:2-Acetylaminofluorene / Q000494:pharmacology; D000818:Animals; D004032:Diet; D004048:Diethylamines / Q000494:pharmacology; D004195:Disease Models, Animal; D005982:Glutathione Transferase / Q000378:metabolism; D007501:Iron / Q000008:administration & dosage* / Q000494:pharmacology; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced*; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D009929:Organ Size; D051381:Rats; D017208:Rats, Wistar
D004048:Diethylamines; D015073:2-Acetylaminofluorene; C034281:diethylamine; D007501:Iron; D005982:Glutathione Transferase