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Pentachlorophenol (but not Phenobarbital) Promotes Intrahepatic Biliary Cysts Induced by Diethylnitrosamine to Cholangio Cystic Neoplasms in B6C3F1 Mice Possibly Due to Oxidative Stress

Division of Pathology, Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan, umemura{at}nihs.go.jp

Yukio Kodama

Division of Toxicology, Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

Keita Kanki

Division of Pathology, Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

Michael J. Iatropoulos

Department of Pathology, New York Medical College, Basic Science Building, Valhalla, New York, New York 10595, USA

Akiyoshi Nishikawa

Division of Pathology, Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

Masao Hirose

Division of Pathology, Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

Gary M. Williams

Department of Pathology, New York Medical College, Basic Science Building, Valhalla, New York, New York 10595, USA

Administration of diethylnitrosamine (DEN) to B6C3F1 mice at low dose (20 ppm) in drinking water for long duration resulted in formation of multifocal cystic biliary lesions in the liver. To investigate the potential of the lesions to be promoted to neoplasias by chemicals, we examined the effects of 2 different types of hepatocarcinogenesis promoters, pentachlorophenol (PCP) and phenobarbital (PB) in B6C3F1 mice. Two weeks' exposure to PCP at a concentration of 600 ppm in the diet increased 8-oxodeoxyguanosine (8-oxodG) levels in liver nuclear DNA, and cell proliferation quantified by bromodeoxyuridine (BrdU) incorporation in epithelial cells of intrahepatic bile ducts as well as hepatocytes. In mice initiated with DEN at 20 ppm in the drinking water for the first 13 weeks followed, after a 4-week recovery interval, by PCP at a concentration of 600 ppm in the diet for 25 weeks, cystic atypical hyperplasias, cholangiomas, and cholangiocarcinomas were present at statistically significant higher incidences. In contrast, neoplasia did not occur in animals treated with 500 ppm PB, and there were no elevations in 8-oxodG levels or increases in the proliferation of biliary epithelium, although proliferation was increased in hepatocytes. These findings suggest that oxidative stress due to PCP might exert a promoting action on the biliary cystic lesions produced by DEN.

Key Words: Pentachlorophenol • diethylnitrosamine • phenobarbital • biliary cysts • cholangioneoplasms • 8-oxydeoxyguanosine • B6C3F1 mice.

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