Hepatocellular carcinoma caused by iron overload: a possible mechanism of direct hepatocarcinogenicity.
OBJECTIVE
Excess hepatic iron may be both directly and indirectly carcinogenic. The aim of this study was to determine if generation of reactive oxygen species and the resulting oxidative damage induced by free hepatic iron is directly hepatocarcinogenic.


METHODS
Sixty male Wistar albino rats were iron-loaded by ferrocene supplementation of their diet. Biochemical parameters of oxidative damage and lipid peroxidation, DNA unwinding and strand breaks, and the Ames Mutagenesis Test were measured at 4 monthly intervals and correlated with the degree of hepatic iron overload, the presence of iron-free preneoplastic foci in the liver, and the development of hepatocellular carcinoma in comparison with 60 control rats.


RESULTS
Levels of lipid hydroperoxides, malonaldehyde, 8-isoprostane and 8-hydroxy-2'-deoxyguanosine increased, reaching peak concentrations at 20-24 months, and correlating with an increase in the rate of DNA unwinding, strand breaks, and positive Ames Tests. Iron-free neoplastic foci became evident at 16 months and thereafter increased in number. Preneoplastic foci were present in five of eight rats remaining at 32 months and HCC had developed in one of the five.


CONCLUSIONS
Our findings are compatible with the hypothesis that the direct hepatocarcinogenic effect of free iron is mediated by the generation of oxygen reactive species and oxidative damage that are mutagenic and carcinogenic.
Asare
George A
GA
MRC/University Molecular Hepatology Research Unit, Department of Medicine, University of the Witwatersrand, 7 York Road, Parktown 2193, Johannesburg, South Africa.
Mossanda
Kensese S
KS
Kew
Michael C
MC
Paterson
Alan C
AC
Kahler-Venter
Christina P
CP
Siziba
Kwanele
K
D000818:Animals; D004249:DNA Damage / Q000187:drug effects; D004265:DNA Helicases / Q000737:chemistry / Q000378:metabolism; D016521:Electrophoresis, Gel, Pulsed-Field; D005470:Fluorometry; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007501:Iron / Q000097:blood / Q000378:metabolism; D019190:Iron Overload / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D009152:Mutagenicity Tests; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012486:Salmonella typhimurium / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D000637:Transaminases / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000378:metabolism
D017382:Reactive Oxygen Species; D000509:alpha-Fetoproteins; D013481:Superoxides; D007501:Iron; D000637:Transaminases; D004265:DNA Helicases