Toxicology. 2006 Feb 15;219(1-3):41-52. Epub 2005 Dec 6. Related
Articles, Links

Hepatocellular carcinoma caused by iron overload: A possible mechanism
of direct hepatocarcinogenicity.

Asare GA, Mossanda KS, Kew MC, Paterson AC, Kahler-Venter CP, Siziba K.

MRC/University Molecular Hepatology Research Unit, Department of
Medicine, University of the Witwatersrand, 7 York Road, Parktown 2193,
Johannesburg, South Africa.

BACKGROUND/AIMS: 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.

PMID: 16337327 [PubMed - in process]

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Alcohol. 2005 Apr;35(3):243-9. Related Articles, Links

Alcohol, iron-associated oxidative stress, and cancer.

Petersen DR.

Department of Pharmaceutical Sciences, Box C238, University of Colorado
Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80262, USA.
dennis.petersen@uchsc.edu

Oxidative stress is recognized to play an important role in the
initiation and promotion events of carcinogenesis. Alcoholic liver
disease is associated with significant oxidative stress as well as the
hepatic accumulation of iron, a transition element also documented to
initiate oxidative stress. The combined prooxidant potential of ethanol
and iron is at least additive and possibly synergistic with respect to
inducing hepatocellular oxidative stress and antioxidant depletion. One
cellular consequence of sustained oxidative stress and redox imbalance
resulting from the combined actions of alcohol and iron is lipid
peroxidation, resulting in the production of aldehydic products such as
4-hydroxy-2-nonenal, which has been linked to site-specific mutations
of the p53 gene. In addition, the accumulation of iron in hepatic
macrophage isolated from laboratory animals chronically ingesting
alcohol is associated with activation of nuclear factor-kappa B and
production of tumor necrosis factor-alpha, providing a proinflammatory
cellular environment also favorable for initiation and promotion of
carcinogenesis. Consequently, there is persuasive evidence that the
potential of ethanol and iron to induce oxidative stress may be an
important pathogenic mechanism for the increased occurrence of
hepatocellular carcinoma in individuals with hepatic iron overload who
ingest alcohol.

Publication Types:
Review

PMID: 16054986 [PubMed - indexed for MEDLINE]

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