Anti-epileptic drug phenytoin enhances androgen metabolism and androgen receptor expression in murine hippocampus.
Epilepsy is very often related to strong impairment of neuronal networks, particularly in the hippocampus. Previous studies of brain tissue have demonstrated that long-term administration of the anti-epileptic drug (AED) phenytoin leads to enhanced metabolism of testosterone mediated by cytochrome P450 (CYP) isoforms. Thus, we speculate that AEDs affect androgen signalling in the hippocampus. In the present study, we investigated how the AED phenytoin influences the levels of testosterone, 17beta-oestradiol, and androgen receptor (AR) in the hippocampus of male C57Bl/6J mice. Phenytoin administration led to a 61.24% decreased hippocampal testosterone level as compared with controls, while serum levels were slightly enhanced. 17beta-Oestradiol serum level was elevated 2.6-fold. Concomitantly, the testosterone metabolizing CYP isoforms CYP3A11 and CYP19 (aromatase) have been found to be induced 2.4- and 4.2-fold, respectively. CYP3A-mediated depletion of testosterone-forming 2beta-, and 6beta-hydroxytestosterone was significantly enhanced. Additionally, AR expression was increased 2-fold (mRNA) and 1.8-fold (protein), predominantly in the CA1 region. AR was shown to concentrate in nuclei of CA1 pyramidal neurons. We conclude that phenytoin affects testosterone metabolism via induction of CYP isoforms. The increased metabolism of testosterone leading to augmented androgen metabolite formation most likely led to enhanced expression of CYP19 and AR in hippocampus. Phenytoin obviously modulates the androgen signalling in the hippocampus.
Meyer
Ralf Peter
RP
Pathologisches Institut, Abt. Neuropathologie, Neurozentrum, Universitätsklinik Freiburg, Freiburg, Germany. ralf.meyer@uniklinik-freiburg.de
Hagemeyer
Christoph Eugen
CE
Knoth
Rolf
R
Kaufmann
Michel Rene
MR
Volk
Benedikt
B
D000728:Androgens / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001141:Aromatase / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D004958:Estradiol / Q000097:blood / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D006900:Hydroxylation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010105:Oxygenases / Q000235:genetics; D010672:Phenytoin / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D013739:Testosterone / Q000097:blood / Q000378:metabolism; D014018:Tissue Distribution
D000728:Androgens; D000927:Anticonvulsants; D008565:Membrane Proteins; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013739:Testosterone; D004958:Estradiol; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D001141:Aromatase; C086292:Cyp2c29 protein, mouse; C496508:Cyp3a11 protein, mouse; C496509:Cyp3a13 protein, mouse; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2