부산대학교 도서관

To authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1471-4159.2009.05994.x Byline: Ralf Peter Meyer (*), Marcel Gehlhaus (*), Ricarda Schwab (,), Carolin Burck (,), Rolf Knoth (*), Christoph Eugen Hagemeyer ([double dagger]) Keywords: androgen receptor; CYP3A/2B; cytochrome P450; mouse brain; PC-12 cells; phenytoin; testosterone metabolism Abstract: Abstract 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 2[alpha]-, 2[beta]-, 6[beta]-, 16[alpha]- and 16[beta]-hydroxytestosterones, while 6[alpha]- and 15[alpha]-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. Author Affiliation: (*)Abteilung Neuropathologie, Neurozentrum, Universitatsklinik Freiburg, Freiburg, Germany ([dagger])Department Mechanical & Process Engineering, Hochschule Furtwangen University, Villingen-Schwenningen ([double dagger])The Baker Heart Research Institute, Melbourne, Victoria, Australia Article History: Received November 10, 2008; revised manuscript received January 28, 2009; accepted February 11, 2009. Article note: Address correspondence and reprint requests to Ralf P. Meyer, PhD, Assistant Professor, Pathologisches Institut, Abt. Neuropathologie, Neurozentrum, Universitat Freiburg, Breisacherstra[sz]e 64, Freiburg D-79106, Germany. E-mail: ralf.meyer@uniklinik-freiburg.de