Androgen receptor antagonist versus agonist activities of the fungicide vinclozolin relative to hydroxyflutamide
| Autor: | Madhabananda Sar, Kelce Wr, Elizabeth M. Wilson, Choi-iok Wong |
|---|---|
| Rok vydání: | 1995 |
| Předmět: |
Agonist
Male medicine.medical_specialty Transcription Genetic medicine.drug_class Biology Transfection Biochemistry Binding Competitive Cell Line Transactivation chemistry.chemical_compound Internal medicine LNCaP medicine Androgen Receptor Antagonists Tumor Cells Cultured Animals Humans Vinclozolin Molecular Biology Oxazoles Reproduction Dihydrotestosterone Cell Biology DNA Flutamide Recombinant Proteins Fungicides Industrial Androgen receptor Kinetics Endocrinology chemistry Receptors Androgen Androgens Androgen Response Element Hydroxyflutamide medicine.drug |
| Zdroj: | The Journal of biological chemistry. 270(34) |
| ISSN: | 0021-9258 |
| Popis: | The mechanism of antiandrogenic activity of vinclozolin (3-(3,5-dichlorophenyl)-5-methyl-5-vinyloxazolidine-2,4-dione), a dicarboximide fungicide under investigation for its potential adverse effects on human male reproduction, was investigated using recombinant human androgen receptor (AR). The two primary metabolites of vinclozolin in plants and mammals are M1 (2-[[3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid) and M2 (3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide). Both metabolites, in a dose-dependent manner, target AR to the nucleus and inhibit androgen-induced transactivation mediated by the mouse mammary tumor virus promoter. M2 is a 50-fold more potent inhibitor than M1 and only 2-fold less than hydroxyflutamide. In the presence of dihydrotestosterone (50 nM), M2 (0.2-10 microM) inhibits androgen-induced AR binding to androgen response element DNA. In the absence of dihydrotestosterone, concentrations of 10 microM M2 or hydroxyflutamide promote AR binding to androgen response element DNA and activation of transcription. Agonist activities of M2 and hydroxyflutamide occur at 10-fold lower concentrations with the mutant AR (Thr877 to Ala) endogenous to LNCaP human prostate cancer cells. The results indicate that androgen antagonists can act as agonists, depending on ligand binding affinity, concentration, and the presence of competing natural ligands. |
| Databáze: | OpenAIRE |
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