Effects of tamoxifen administration on the expression of xenobiotic metabolizing enzymes in rat liver
| Autor: | E F, Nuwaysir, Y P, Dragan, C R, Jefcoate, V C, Jordan, H C, Pitot |
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| Rok vydání: | 1995 |
| Předmět: |
Epoxide Hydrolases
Male Sex Characteristics Base Sequence Dose-Response Relationship Drug Molecular Sequence Data Gene Expression Breast Neoplasms Rats Inbred F344 Rats Xenobiotics Isoenzymes Tamoxifen Cytochrome P-450 Enzyme System Liver Cytochrome P-450 CYP1A2 Steroid Hydroxylases Microsomes Liver Animals Humans Female Aryl Hydrocarbon Hydroxylases RNA Messenger DNA Probes Oxidoreductases |
| Zdroj: | Cancer research. 55(8) |
| ISSN: | 0008-5472 |
| Popis: | The nonsteroidal antiestrogen tamoxifen is widely used in breast cancer treatment and is currently under evaluation as a chemopreventive agent for individuals at high risk of contracting the disease. The effects of tamoxifen administration on the expression of xenobiotic metabolizing enzymes in F344 rat liver have been investigated. Tamoxifen administration for 7 days produced a dose-dependent increase in enzyme expression similar to that reported to be produced by phenobarbital. Increases in CYPIIB1, CYPIIB2, CYPIIIA, and microsomal epoxide hydrolase mRNA and protein levels in males and females were observed by Western and Northern blotting. The expression of CYPIA1, CYPIA2, and gamma-glutamyl transpeptidase mRNA was not significantly affected by tamoxifen treatment. Tamoxifen was approximately one-tenth as potent an inducer of combined CYPIIB1/2 mRNA compared with phenobarbital when the two drugs were administered at equimolar doses. In addition to the effects observed after short-term tamoxifen exposure, increases in CYPIIB1 and CYPIIB2 protein levels were noted after 6 and 15 months of 250 ppm tamoxifen in the diet. Taken together, these results suggest that tamoxifen is a weak phenobarbital-like inducer. However, there are significant differences in the induction profiles produced by the two drugs. Most significant of these differences was the relatively weak induction of CYPIIB1 but striking induction of CYPIIB2 by tamoxifen. In addition, females were often more sensitive than males to tamoxifen, especially at low doses. These differences suggest that tamoxifen and phenobarbital do not use identical molecular mechanisms to produce enzyme induction. It is possible that the effects of tamoxifen are a result of phenobarbital-like properties coupled with the effects of tamoxifen-induced hormonal perturbations in the animal. In sum, tamoxifen induces enzyme expression in rats at a dose comparable, on a mg/kg basis, to the dose women receive for disease management, suggesting these results may be significant for human exposure. |
| Databáze: | OpenAIRE |
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