Carcinogenesis, Vol. 23, No. 3, 491-498,
March 2002
© 2002 Oxford University Press
CARCINOGENESIS |
Change in the gene expression of hepatic tamoxifen-metabolizing enzymes during the process of tamoxifen-induced hepatocarcinogenesis in female rats
Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan,
1 Institute of Applied Biochemistry, University of Tsukuba, 1-1-1, Tennodai, Tsukuba City, Ibaraki 305-8572, Japan and
2 First Department of Biochemistry, Saitama Medical School, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan
Altered gene expression of the enzymes responsible for tamoxifen metabolism during the process of tamoxifen-induced hepatocarcinogenesis in female Sprague–Dawley rats was examined by the RT–PCR method. Treatment of rats with tamoxifen (20 mg/kg body/day) for 52 weeks, but not the 1 day, 2 or 12 week treatments, resulted in the formation of the liver hyperplastic nodules. The gene expression of CYP3A subfamily enzymes, especially CYP3A1, responsible for not only detoxification (N-demethylation) but also activation (
-hydroxylation) of tamoxifen, was increased by the tamoxifen treatments for 2 and 12 weeks, whereas after the 52 week treatment, the expression in the induced nodules returned to the control level. The gene expression of SULT2A subfamily sulfotransferases, especially HSTa, responsible for metabolic activation of -hydroxytamoxifen was decreased to a level <20% of the control in the nodules, although no significant change in the expression was observed in the liver of rats treated with tamoxifen for 1 day, 2 or 12 weeks. On the other hand, the gene expression of CYP3A2 and flavin-containing monooxygenase 1 (FMO1), responsible for the N-demethylation and N-oxidation, respectively, of tamoxifen was increased in a time-dependent fashion up to the 52 week treatment. Although the gene expression of UDP-glucuronosyltransferase(s), which might be responsible for detoxification of tamoxifen, was also increased by the tamoxifen treatment for 2 or 12 weeks, it decreased to the control level in the nodules after the 52 week treatment. The present findings demonstrate that in the early stage of the formation of the liver hyperplastic nodules by tamoxifen, the genes of the enzymes responsible for not only detoxification but also activation of tamoxifen were activated, whereas in the later stage (in the nodules), the genes of the detoxification enzymes, CYP3A2 and FMO1, remained active, but those of the activation enzymes such as CYP3A1 and HSTa were suppressed.
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