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J.Health Sci., 51(2), 185-190, 2005
Increased Expression of Cyclin-Dependent Kinase-Interacting Protein p21 during Tamoxifen-Induced Hepatocarcinogenesis in Female Rats
Toshihiko Kasahara,a Chihaya
Kakinuma,b Chitose
Kuwayama,b Masamichi
Hashiba,a Tsuyoshi
Harada,c and Masakuni
Degawa*, a
aDepartment of Molecular Toxicology and COE Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka,
52-1 Yada, Shizuoka 422-8526, Japan, bDepartment of Pathology, Juntendo University, School of Medicine, 2-1-1 Hongo,
Bunkyo-ku, Tokyo 113-8421, Japan, and cFirst Department of Biochemistry, Saitama Medical School, 38 Morohongo, Moroyama-machi,
Iruma-gun, Saitama 350-0495, Japan
Female Sprague-Dawley rats were given a single dose of tamoxifen (20 mg/kg body weight) by gavage or the
same dose at 24-hr intervals for 2, 12, or 52 weeks, and the altered expression of cyclin-dependent kinase-interacting
protein p21 (p21), tumor suppression protein p53, and the placental form of glutathione S-transferase (GST-P) in the
liver was comparatively examined during the process of tamoxifen-induced hepatocarcinogenesis. The development
of hepatocellular carcinoma was histopathologically observed only in rats administered tamoxifen for 52 weeks, but
not in any other experimental groups. Significant increases in levels of the mRNA and protein of p21 were first
observed in rats administered tamoxifen for 2 weeks, and the levels increased with further long-term treatment.
Immunohistochemical analyses of p21 and GST-P in the liver of rats administered tamoxifen for 12 and 52 weeks
revealed that the localization of p21-positive cells did not necessarily coincide with that of GST-P-positive cells. In
the 52-week group, p21-positive cells, rather than GST-P-positive cells, were observed preferentially in the region
consisting of histopathologically malignant cells. The present study demonstrated that during the process of
tamoxifen-induced hepatocarcinogenesis, expression levels of the mRNA and protein of p21 were increased. The significance
of the increased expression of p21 during hepatocarcinogenesis is discussed.
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