Cell proliferation induced by 3,3′,5-triiodo-L-thyronine is associated with a reduction in the number of preneoplastic hepatic lesions

• Published in: Carcinogenesis (New York) 1999-12, Vol.20 (12), p.2299-2304
• Main Authors: Ledda-Columbano, G.M., Perra, A., Piga, R., Pibiri, M., Loi, R., Shinozuka, H., Columbano, A.
• Format: Article
• Language: English
• Subjects: 2-AAF; 2-acetylaminofluorene; 5-triiodo-l-thyronine; Animal tumors. Experimental tumors; Animals; Biological and medical sciences; BrdU; bromodeoxyuridine; Cell Division - drug effects; DENA; diethylnitrosamine; Experimental digestive system and abdominal tumors; glutathione S-transferase placental form; Glutathione Transferase - metabolism; GSTP; labelling index; Liver Neoplasms, Experimental - enzymology; Liver Neoplasms, Experimental - prevention & control; Male; Medical sciences; Mitogens - pharmacology; partial hepatectomy; peroxisome proliferator-activated receptor; peroxisome proliferators; PPAR; Precancerous Conditions - enzymology; Precancerous Conditions - prevention & control; Rats; Rats, Inbred F344; Rats, Wistar; resistant hepatocyte; retinoic acid receptor; RXR; T3 receptor; Triiodothyronine - pharmacology; Tumors
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/20.12.2299

Previous studies have suggested that liver cell proliferation is fundamental for the growth of carcinogen-initiated cells. To gain further information on the association between cell proliferation and hepatocarcinogenesis, we have examined the effect of the hormone 3,3′,5-triiodo-L-thyronine (T3), a strong liver mitogen, on the growth of diethylnitrosamine (DENA)-induced hepatic lesions positive for the placental form of glutathione S-transferase (GSTP). Two weeks after a single initiating dose of DENA (150 mg/kg), cycles of liver cell proliferation were induced in male Fischer rats by feeding a T3-supplemented diet (4 mg/kg) 1 week/month for 7 months. Rats were killed at the end of the seventh cycle or 1 month later. Results indicate that, in spite of an increased labelling index, a 70% reduction in the number/cm2 of GSTP-positive minifoci occurred in T3-treated rats. A decrease in the number of GSTP-positive foci was also observed in T3-treated rats killed 1 month after the last exposure to the hormone (40, versus 67 foci/cm2 in controls), indicating that the reduction was not due to an inhibitory effect on GSTP exerted by the concomitant presence of T3. In a second series of experiments where DENA-treated rats were fed T3 for 1 week and then subjected to the resistant hepatocyte (RH) model, it was found that T3 treatment prior to promotion resulted in a decrease in the number of GSTP-positive foci (16 GSTP+ foci/cm2 in T3-fed animals versus 45 in the control group). The results indicate that cell proliferation associated with T3 treatment: (i) reduces the number of carcinogen-induced GSTP-positive lesions; (ii) does not exert any differential effect on the growth of the remaining foci; (iii) inhibits the capacity of putative DENA-initiated cells to be promoted by the RH model. Data suggest that cell proliferation may not necessarily represent a stimulus for the growth of putative preneoplastic lesions.