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ToxSci Advance Access published online on November 24, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi044
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received September 19, 2004
Accepted November 17, 2004

Carcinogenicity

Different Inhibitory Effects in Early- and Late-Phase of Treatment with KAT-681, a Liver-Selective Thyromimetic, on Rat Hepatocarcinogenesis Induced by 2-Acetylaminofluorene and Partial Hepatectomy After Diethylnitrosamine Initiation

Morimichi Hayashi 1*, Toru Tamura 2, Junji Kuroda 2, Hideki Ohnota 3, Nobuo Shibata 4, Masuo Akahane 3, Yoko Kashida 5, and Kunitoshi Mitsumori 5

1 Toxicology Laboratories, Research and Development, Kissei Pharmaceutical Co. Ltd., Hotaka, Minamiazumi-gun, Nagano 399-8305, Japan; United Graduate School of Veterinary Science, Gifu University, Gifu 501-1193, Japan
2 Toxicology Laboratories, Research and Development, Kissei Pharmaceutical Co. Ltd., Hotaka, Minamiazumi-gun, Nagano 399-8305, Japan
3 Central Research Laboratories, Research and Development, Kissei Pharmaceutical Co. Ltd., Hotaka, Minamiazumi-gun, Nagano 399-8305, Japan
4 Central Research Laboratories, Research and Development, Research and Development, Kissei Pharmaceutical Co. Ltd., Hotaka, Minamiazumi-gun, Nagano 399-8305, Japan
5 Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan

* To whom correspondence should be addressed.
Morimichi Hayashi, E-mail: morimichi_hayashi{at}pharm.kissei.co.jp


  Abstract

We recently reported that short-term treatment with KAT-681 (KAT), a liver-selective thyromimetic, inhibits the development of preneoplastic lesions in rat livers, and may be a candidate as chemopreventive agents for hepatocarcinogenesis. In this study, time-course observations of the hepatocellular proliferative lesions were performed during short- and long-term treatment of KAT to further investigate the anti-hepatocarcinogenic effects. The hepatocellular proliferative lesions in male F344 rats were induced by the initiation treatment of diethylnitrosamine (DEN), followed by treatment of 2-acetylaminofluorene (2-AAF) and partial hepatectomy (PH). The rats were administered orally with KAT at a dose of 0.25 mg/kg/day for 3 weeks (experiment 1) or 0.1 mg/kg/day for 20 weeks (experiment 2). In experiment 1, a serial reduction in the number of altered hepatocellular foci (AHFs) with positive expression of glutathione S-transferase placental form (GST-P) was observed until day 14 of the treatment period. The proliferative index (PI) of hepatocytes in the AHFs significantly increased in the KAT group throughout the treatment period with a peak on day 2. KAT treatment showed no obvious effects on GST-P-positive hepatocellular adenomas (HCAs) at any time point. On the other hand, long-term KAT treatment in experiment 2 revealed a reduction in the mean size of HCAs in addition to reductions in the number and mean size of AHFs. The PIs within these lesions in KAT-treated rats were significantly lower than those in controls. The present study indicates that KAT has different inhibitory effects on hepatocarcinogenesis in the early- and late-phases of KAT treatment; there is a reduction in AHFs with enhanced cell proliferation in the early-phase and the inhibition of development of AHFs and HCAs with suppression of cell proliferation in the late-phase. These results may suggest further potential of KAT as a promising chemopreventive agent for hepatocarcinogenesis.

Keywords: hepatocarcinogenesis; thyromimetic; thyroid hormone; chemoprevention; cell proliferation; rat.
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