Vitamin E reduces chromosomal damage and inhibits hepatic tumor formation in a transgenic mouse model.
We have previously shown that chronic activation of mitogenic signaling induced by over-expression of c-myc and transforming growth factor-alpha (TGFalpha) transgenes in mouse liver induces a state of oxidative stress. We therefore proposed that increased reactive oxygen species (ROS) generation might be responsible for the extensive chromosomal damage and acceleration of hepatocarcinogenesis characteristic for TGFalpha/c-myc mice. In this study, we show that vitamin E (VE), a potent free radical scavenging antioxidant, is able to protect liver tissue against oxidative stress and suppress tumorigenic potential of c-myc oncogene. Dietary supplementation with VE, starting from weaning, decreased ROS generation coincident with a marked inhibition of hepatocyte proliferation while increasing the chromosomal as well as mtDNA stability in the liver. Similarly, dietary VE reduced liver dysplasia and increased viability of hepatocytes. At 6 mo of age, VE treatment decreased the incidence of adenomas by 65% and prevented malignant conversion. These results indicate that ROS generated by over-expression of c-myc and TGFalpha in the liver are the primary carcinogenic agents in this animal model. Furthermore, the data demonstrate that dietary supplementation of VE can effectively inhibit liver cancer development.
Factor
V M
VM
Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Laskowska
D
D
Jensen
M R
MR
Woitach
J T
JT
Popescu
N C
NC
Thorgeirsson
S S
SS
D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology*; D004249:DNA Damage; D004272:DNA, Mitochondrial; D019587:Dietary Supplements; D004195:Disease Models, Animal; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000031:analogs & derivatives*
D000975:Antioxidants; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D014810:Vitamin E; D024502:alpha-Tocopherol; D024505:Tocopherols