Diet restriction increases ubiquinone contents and inhibits progression of hepatocellular carcinoma in the rat.
BACKGROUND
The aim of the present study was to evaluate the effect of a moderate diet restriction on the progression of preneoplastic foci into hepatocellular carcinomas (HCCs) and whether such an effect was related to altered cell proliferation, apoptosis, and/or tumour contents of lipid-soluble antioxidants.


METHODS
Male Wistar rats were exposed to diethylnitrosamine as initiator and 2-acetylaminofluorene plus partial hepatectomy as promoter. Six weeks after initiation the animals were given a diet restricted to 75%-80% of that given to controls until being killed 45 weeks later. Macroscopic liver tumours were histologically classified. In hepatocellular carcinomas the numbers of S-phase (labelling index) and DNA-fragmented (apoptotic index) nuclei were calculated immunohistochemically, and the tumour contents of alpha-tocopherol and ubiquinone were determined.


RESULTS
The number of animals with HCC and the number of HCCs per animal were significantly reduced in restricted-diet animals compared with controls. In HCCs the contents of ubiquinone-9 and -10 were significantly increased, labelling indices were enhanced 3-fold, and apoptotic indices 12-fold as a response to food restriction. Neither the size nor the differentiation of HCCs was altered by food restriction. The numbers and areas of preneoplastic foci were similar in restricted-diet animals compared with those of controls.


CONCLUSIONS
Moderate, long-term food restriction inhibits the progression of preneoplastic liver foci into HCC. Possible mechanisms of this inhibition are a shift in the balance between apoptosis and cell division towards cell death and an adaptive response to oxidative stress by increased tumour contents of ubiquinones.
Wang
G S
GS
Dept. of Pathology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
Olsson
J M
JM
Eriksson
L C
LC
Stål
P
P
D015073:2-Acetylaminofluorene; D000818:Animals; D000975:Antioxidants / Q000032:analysis; D017209:Apoptosis; D002273:Carcinogens; D002455:Cell Division; D004052:Diethylnitrosamine; D018450:Disease Progression; D002149:Energy Intake; D005982:Glutathione Transferase / Q000032:analysis; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D014451:Ubiquinone / Q000378:metabolism*; D014810:Vitamin E / Q000032:analysis
D000975:Antioxidants; D002273:Carcinogens; D014451:Ubiquinone; D014810:Vitamin E; D004052:Diethylnitrosamine; D015073:2-Acetylaminofluorene; D005982:Glutathione Transferase