Potential Beneficial Metabolic Interactions Between Tamoxifen and Isoflavones via Cytochrome P450-mediated Pathways in Female Rat Liver Microsomes
| Autor: | Steven C. Halls, Joshua F. Alfaro, Ming Hu, Jun Chen, Zhaohui Zhou |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
medicine.medical_specialty
Pharmaceutical Science Genistein Antineoplastic Agents In Vitro Techniques Pharmacology Inhibitory postsynaptic potential Rats Sprague-Dawley chemistry.chemical_compound Cytochrome P-450 Enzyme System Internal medicine medicine Animals Cytochrome P-450 Enzyme Inhibitors Drug Interactions Pharmacology (medical) Enzyme Inhibitors skin and connective tissue diseases Chromatography High Pressure Liquid biology Organic Chemistry Cytochrome P450 Isoflavones Drug interaction Rats Tamoxifen Endocrinology chemistry Microsomes Liver biology.protein Microsome Molecular Medicine Female Algorithms hormones hormone substitutes and hormone antagonists Biotechnology medicine.drug |
| Zdroj: | Pharmaceutical Research. 21:2095-2104 |
| ISSN: | 0724-8741 |
| DOI: | 10.1023/b:pham.0000048202.92930.61 |
| Popis: | This study aims to evaluate a cytochrome P450-based tamoxifen-isoflavone interaction and to determine the mechanisms responsible for inhibitory effects of isoflavones (e.g., genistein) on the formation of alpha-hydroxytamoxifen.Metabolism studies were performed in vitro using female rat liver microsomes. The effects of genistein and an isoflavone mixture on tamoxifen metabolism and the inhibition mechanism were determined using standard kinetic analysis, preincubation, and selective chemical inhibitors of P450.Metabolism of tamoxifen was saturable with Km values of 4.9+/-0.6, 14.6+/-2.2, 25+/-5.9 microM and Vmax values of 34.7+/-1.4, 297.5+/-19.2, 1867+/-231 pmol min(-1) mg(-1) for a-hydroxylation, N-desmethylation, and N-oxidation, respectively. Genistein (25 microM) inhibited alpha-hydroxylation at 2.5 microM tamoxifen by 64% (p0.001) but did not affect the 4-hydroxylation, N-desmethylation, and N-oxidation. A combination of three (genistein, daidzein, and glycitein) to five isoflavones (plus biochanin A and formononetin) inhibited tamoxifen alpha-hydroxylation to a greater extent but did not decrease the formation of identified metabolites. The inhibition on alpha-hydroxylation by genistein was mixed-typed with a Ki, value of 10.6 microM. Studies using selective chemical inhibitors showed that tamoxifen alpha-hydroxylation was mainly mediated by rat CYP1A2 and CYP3A1/2 and that genistein 3'-hydroxylation was mainly mediated by rat CYP1A2, CYP2C6 and CYP2D1.Genistein and its isoflavone analogs have the potential to decrease side effects of tamoxifen through metabolic interactions that inhibit the formation of a-hydroxytamoxifen via inhibition of CYP1A2. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink