Inhibitory effects of KAT-681, a liver-selective thyromimetic, on development of hepatocellular proliferative lesions in rats induced by 2-acetylaminofluorene and partial hepatectomy after diethylnitrosamine initiation.
To examine the potential inhibitory effects of a novel liver-selective thyromimetic, KAT-681 (KAT), on the development of hepatocellular proliferative lesions, male F344 rats were given a single intraperitoneal injection of 150 mg/kg diethylnitrosamine (DEN), followed by gavage administration of 7.5 mg/kg per day of 2-acetylaminofluorene (2-AAF) twice daily from weeks 2 to 4 with partial hepatectomy (PH) at week 3. From 5 weeks after the completion of 2-AAF administration, the rats were orally dosed with 0.04, 0.1, or 0.25 mg/kg per day KAT for 3 weeks, and subjected to morphometric analysis of the induced glutathione S-transferase placental form (GST-P)-positive lesions and hepatocellular adenomas (HCAs). Administration of KAT significantly and dose-dependently reduced the total area of GST-P-positive lesions (by 34-48%) and also their numbers (by 20-44%), their mean size not being significantly changed. No effects on the number of HCAs were apparent, although a reduction in their mean size was detected at a dose of 0.25 mg/kg per day KAT (by 34%). On biochemical analysis, serum activity of gamma-glutamyl transpeptidase, an enzyme related to hepatocarcinogenesis, was markedly reduced in rats given 0.25 mg/kg per day KAT (by 64%). The results of the present study thus suggest that KAT inhibits the development of altered hepatocellular foci and might be a promising chemopreventive agent for hepatocarcinogenesis.
Hayashi
Morimichi
M
Toxicology Laboratories, Research and Development, Kissei Pharmaceutical Co. Ltd., 2320-1 Maki, Hotaka, Minamiazumi-gun, 399-8305 Nagano, Japan. morimichi_hayashi@pharm.kissei.co.jp
Ohnota
Hideki
H
Tamura
Toru
T
Kuroda
Junji
J
Shibata
Nobuo
N
Akahane
Masuo
M
Moriwaki
Hisataka
H
Machida
Noboru
N
Mitsumori
Kunitoshi
K
D015073:2-Acetylaminofluorene / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D004052:Diethylnitrosamine / Q000633:toxicity*; D004435:Eating / Q000187:drug effects; D005982:Glutathione Transferase / Q000378:metabolism; D006498:Hepatectomy; D022781:Hepatocytes / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008314:Malonates / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D010647:Phenyl Ethers / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013961:Thyroid Gland / Q000187:drug effects*
D002273:Carcinogens; D008314:Malonates; C496199:N-(4-(3-((4-fluorophenyl)hydroxymethyl)-4-hydroxyphenoxy)-3,5-dimethylphenyl) malonamic acid sodium; D010647:Phenyl Ethers; D018809:Proliferating Cell Nuclear Antigen; D004052:Diethylnitrosamine; D015073:2-Acetylaminofluorene; D005982:Glutathione Transferase