Role of activation of ornithine decarboxylase and DNA synthesis on ethynylestradiol-induced hepatocarcinogenesis.
We have established an animal model for estrogen-induced hepatocarcinogenesis by oral administration of synthetic hormone to female Wistar rats. Daily treatment of rats with 0.15 mg of ethynylestradiol (EE) for 4 months resulted in the development of hyperplastic foci in all animals. At 12 months of EE treatment, four of the 13 rats (30.8%) developed hepatocellular carcinoma. Ornithine decarboxylase (ODC) activity and DNA synthesis in the liver were activated by a single administration of EE, reaching peak levels at 12 and 48 h respectively. The EE-activated peak levels of both ODC activity and DNA synthesis were markedly elevated at 2 months after consecutive treatment, indicating that the female sex hormone stimulates the cellular proliferation during the initiation phase of carcinogenesis. The activities then gradually decreased, but with the levels higher than those in the controls. On the other hand, simultaneous treatment of rats with tamoxifen completely suppressed the EE-induced ODC activity, hepatic foci formation and hepatocellular carcinoma development. Together with our previous findings of DNA adducts and 8-hydroxydeoxyguanosine formation in the early stage of EE-induced carcinogenesis resulting in DNA damage, the present results suggest that estrogen enhanced ODC activity which was followed by increased DNA synthesis (DNA replication). Moreover, these effects might increase misreading during damaged DNA replication and were closely related to initiation, promotion and progression of hepatocarcinogenesis in this experimental model.
Machishi
H
H
First Department of Surgery, Mie University Faculty of Medicine, Japan.
Higashi
S
S
Hibasami
H
H
Nakashima
K
K
Kawarada
Y
Y
Mizumoto
R
R
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000494:pharmacology*; D004261:DNA Replication / Q000502:physiology*; D004789:Enzyme Activation; D004790:Enzyme Induction; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D005260:Female; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D009955:Ornithine Decarboxylase / Q000096:biosynthesis / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D002273:Carcinogens; D004997:Ethinyl Estradiol; D009955:Ornithine Decarboxylase