Concordant up-regulation of cytochrome P450 Cyp3a11, testosterone oxidation and androgen receptor expression in mouse brain after xenobiotic treatment
| Autor: | Marcel Gehlhaus, Christoph E. Hagemeyer, Rolf Knoth, Ricarda Schwab, Ralf Peter Meyer, Carolin Bürck |
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| Rok vydání: | 2009 |
| Předmět: |
Male
medicine.medical_specialty Time Factors medicine.drug_class CYP3A medicine.medical_treatment Central nervous system Biology Pharmacology Biochemistry PC12 Cells Gene Expression Regulation Enzymologic Xenobiotics Cellular and Molecular Neuroscience Mice Limbic system Internal medicine medicine Animals Cytochrome P-450 CYP3A Testosterone Cytochrome P450 Brain Membrane Proteins Androgen Rats Up-Regulation Androgen receptor Mice Inbred C57BL Steroid hormone medicine.anatomical_structure Endocrinology Hypothalamus Receptors Androgen Inactivation Metabolic biology.protein Oxidation-Reduction |
| Zdroj: | Journal of neurochemistry. 109(2) |
| ISSN: | 1471-4159 |
| Popis: | Inactivation of testosterone by specific hydroxylations is a main function of cytochrome P450 (P450, CYP) in the brain. Recent data imply that induction of brain P450s by neuroactive drugs alters steroid hormone levels and endocrine signalling, giving rise to endocrine disorders. In this study, we investigated this drug-hormone crosstalk in mouse brain. Phenytoin led to a significant increase of 2alpha-, 2beta-, 6beta-, 16alpha- and 16beta-hydroxytestosterones, while 6alpha- and 15alpha-hydroxytestosterones showed no significant alteration of their metabolism compared with untreated controls. Inhibition of testosterone hydroxylation using the chemical inhibitors orphenadrine, chloramphenicol, ketoconazole and nifedipine as well as antibodies against CYP3A- and 2B-isoforms pointed to major role of Cyp3a11 and an only minor function of Cyp2b9/10 in mouse brain. Cyp3a11 revealed to be the major isoform affected by phenytoin. There was considerable overlap of Cyp3a11 and AR expression in neuronal structures of the limbic system, namely the hippocampus, amygdala, hypothalamus and thalamus. Phenytoin treatment led to an increase of both, Cyp3a11 and AR expression in the limbic system. Additionally, the coherence between CYP3A and AR expression was analysed in PC-12 cells. Inhibition of phenytoin-induced endogenous CYP3A2 and AR by ketoconazole led a reduction of their expression to basal levels. We conclude that Cyp3a11 plays a crucial role in directing drug action to hormonal response within the limbic system of mouse brain in a so-called drug-hormone crosstalk. |
| Databáze: | OpenAIRE |
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