Carcinogenesis, Vol. 20, No. 6, 1115-1120,
June 1999
© 1999 Oxford University Press
Carcinogenesis |
Pentachlorophenol (PCP) produces liver oxidative stress and promotes but does not initiate hepatocarcinogenesis in B6C3F1 mice
Division of Toxicology,
1 Division of Risk Assessment and
2 Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan,
3 Faculty of Living Sciences, Showa Women's University, 1-7 Taishido, Setagaya-ku, Tokyo 154-8571, Japan and
4 American Health Foundation, One Dana Road, Valhalla, NY 10595, USA
To elucidate the mechanism of hepatocarcinogenesis of pentachlorophenol (PCP) in mice, critical effects related to carcinogenicity were studied in the livers of B6C3F1 male mice administered PCP at concentrations of 600 and 1200 p.p.m. in the diet for 8 weeks. Oxidative stress was assessed by measurements of 8-oxodeoxyguanosine (8-oxodG) in the liver nuclear DNA and hepatocyte cell proliferation was quantified by bromodeoxyuridine incorporation. Also, initiation and promotion were assessed in a two-stage hepatocarcinogenesis model in which one group of mice was given PCP at concentrations of 600 and 1200 p.p.m. as initiator for the first 13 weeks with subsequent administration of phenobarbital (PB) as promoter at a concentration of 500 p.p.m. in the drinking water for 29 weeks. A second group was initiated with diethylnitrosamine (DEN) at 20 p.p.m. in the drinking water for the first 13 weeks followed after a 4 week recovery interval by PCP at concentrations of 300 and 600 p.p.m. in the diet for 25 weeks. Significant elevations in 8-oxodG levels and cell proliferation were observed in a dose-dependent manner. Incidences and multiplicities of hepatocellular tumors in mice treated with PCP after DEN initiation were increased compared with those in mice given initiation only. In contrast, in mice given PCP as initiator followed by PB no enhancement of neoplastic lesions occurred. These findings are interpreted to demonstrate that PCP exerts a promoting action, but not an initiating effect on liver carcinogenesis and that the promoting action is related to oxidative stress and compensatory hepatocellular proliferation.
Abbreviations: BrdU, bromodeoxyuridine; DEN, diethylnitrosamine; dG, deoxyguanosine; HAF, hepatocellular altered foci; H&E, hematoxylin and eosin; 8-oxodG, 8-hydroxydeoxyguanosine; PB, phenobarbital; PCP, pentachorophenol; RF, replicating fraction; TCHQ, tetrachlorohydroquinone.
5 Present address: New York Medical College, Valhalla, NY 10595, USA
6 To whom correspondence should be addressed Email: umemura{at}nihs.go.jp
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