title: Change in the gene expression of hepatic tamoxifen-metabolizing enzymes during the process of tamoxifen-induced hepatocarcinogenesis in female rats.
abstract: 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 (alpha-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 alpha-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.
authors.affiliation: Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kasahara
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hashiba
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Harada
authors.forename: Masakuni
authors.initials: M
authors.lastname: Degawa
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D014453:Glucuronosyltransferase / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D010105:Oxygenases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015238:Sulfotransferases / Q000378:metabolism; D013629:Tamoxifen / Q000378:metabolism* / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D007527:Isoenzymes; D012333:RNA, Messenger; D013629:Tamoxifen; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D014453:Glucuronosyltransferase; D015238:Sulfotransferases; C028152:alcohol sulfotransferase