Role of reactive oxygen in synthetic estrogen induction of hepatocellular carcinomas in rats and preventive effect of vitamins.
We have established an experimental model of oral contraceptive-induced hepatocellular carcinomas (HCCs) in female Wistar rats, revealing that ethynylestradiol (EE) and norethindrone acetate have actions as both initiators and promoters. The present time-sequence study was undertaken to clarify the role of free radicals in estrogen induction of HCC by measuring detoxifying enzyme activities and levels of 8-hydroxydeoxyguanosine (8-OH-dG) and by assessing the effects of concomitant vitamin C, vitamin E or beta-carotene administration on hepatocarcinogenesis. During 12 months oral administration of EE (0.075 or 0.75 mg/day), the 8-OH-dG levels reached peak values after 1 month, when they were significantly elevated as compared with the controls. Glutathione peroxidase demonstrated a tendency to decrease. Histologically, pre-neoplastic lesions assessed by immunohistochemical staining for placental glutathione S-transferase (GST-P) were first observed at 2 months in the groups given 0.075 and 0.75 mg/day of EE alone, with incidences of HCC at 12 months being 8.7% and 38.5% respectively. Combined administration of vitamins with 0.075 mg EE/day reduced the elevation of the 8-OH-dG levels. GST-P-positive lesions were first observed at 4 months in the vitamin E group and at 6 months in the vitamin C and beta-carotene groups. As compared with the value in the 0.075 mg EE alone group, vitamin administration significantly reduced the numbers of GST-P-positive foci after 12 months of treatment. The incidences of HCC at 12 months were 0% in the vitamin C group, 4.5% in the vitamin E group and 4.8% in the beta-carotene group, i.e. administration of the vitamins inhibited the development of GST-P-positive foci, with suppression of HCC. The results thus suggest that free radicals play an important role in the induction of HCC by estrogen.
Ogawa
T
T
First Department of Surgery, Mie University School of Medicine, Japan.
Higashi
S
S
Kawarada
Y
Y
Mizumoto
R
R
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000627:therapeutic use*; D002338:Carotenoids / Q000627:therapeutic use*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D045166:Estradiol Congeners / Q000378:metabolism* / Q000633:toxicity*; D005260:Female; D005609:Free Radicals / Q000378:metabolism / Q000633:toxicity; D005979:Glutathione Peroxidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000032:analysis; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000517:prevention & control*; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism* / Q000633:toxicity*; D014810:Vitamin E / Q000627:therapeutic use*; D019207:beta Carotene
D016588:Anticarcinogenic Agents; D045166:Estradiol Congeners; D005609:Free Radicals; D017382:Reactive Oxygen Species; D019207:beta Carotene; D014810:Vitamin E; D002338:Carotenoids; D000080242:8-Hydroxy-2'-Deoxyguanosine; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; D003849:Deoxyguanosine; D001205:Ascorbic Acid