title: Lack of promoting effects of phenobarbital at low dose on diethylnitrosamine-induced hepatocarcinogenesis in TGF-alpha transgenic mice.
abstract: Phenobarbital (PB), a rodent non-genotoxic carcinogen, showed hormesis, biphasic effects on rat liver carcinogenesis. To test the hypothesis that the hormesis earlier observed for PB induced hepatocarcinogenesis might also exist in the TGF-alpha transgenic mice model, one which is highly susceptible to carcinogenesis, the carcinogenic or promotion effects of a wide range of phenobarbital (PB) concentrations were investigated. Two weeks after a single i.p. dose of 5 mg /kg bw of diethylnitrosamine (DEN) to 15 day old mice, animals were treated with diet containing PB at doses of 0, 2, 15 or 500 ppm. The incidence and multiplicity of tumors, including hepatocellular adenomas and carcinomas, were significantly increased by the high dose of PB, but no significant difference among the groups receiving 2 and 15 ppm for liver tumors when compared to DEN alone group. The proliferating cell nuclear antigen indices for liver tumors and surrounding hepatocytes in high dose PB treated mice were significantly increased, but no change was noted at the lower doses. The total cytochrome P450 content in the liver was also elevated by 500 ppm of PB, while hepatic 8-OHdG levels demonstrated no significant change. In conclusion, PB at high dose enhances DEN-induced hepatocarcinogenesis in TGF-alpha transgenic mice, but low doses lack any significant effects. One possible mechanism of phenobarbital carcinogenicity might be influenced by cytochrome P450 system exhibiting a strong promoting activity for liver of mice.
authors.affiliation: Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Osaka 545-8585, Japan.
authors.forename: Rawiwan
authors.initials: R
authors.lastname: Puatanachokchai
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kakuni
authors.forename: Hideki
authors.initials: H
authors.lastname: Wanibuchi
authors.forename: Anna
authors.initials: A
authors.lastname: Kinoshita
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Kang
authors.forename: Elsayed I
authors.initials: EI
authors.lastname: Salim
authors.forename: Keiichirou
authors.initials: K
authors.lastname: Morimura
authors.forename: Seiko
authors.initials: S
authors.lastname: Tamano
authors.forename: Glenn T
authors.initials: GT
authors.lastname: Merlino
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukushima
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000633:toxicity*; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D004052:Diethylnitrosamine / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010634:Phenobarbital / Q000008:administration & dosage / Q000633:toxicity*; D016211:Transforming Growth Factor alpha / Q000235:genetics
chemical_list: D000927:Anticonvulsants; D002273:Carcinogens; D016211:Transforming Growth Factor alpha; D004052:Diethylnitrosamine; D010634:Phenobarbital