Modulation of androgen and estrogen receptor expression by antiepileptic drugs and steroids in hippocampus of patients with temporal lobe epilepsy.
OBJECTIVE
Many of the antiepileptic drugs (AED) used in therapy of temporal lobe epilepsy (TLE) are known as cytochrome P450 (CYP, P450) inducers. These AEDs are thought to modulate androgen and estrogen pathways in hippocampus, and therefore cause mental and reproductive disorders found in TLE patients. In the present study, we analyzed expression of androgen receptor (AR), estrogen receptor alpha (ERalpha), and CYP3A in the hippocampus of TLE patients and in murine hippocampal cell line HN25.1.


METHODS
Patients and cell lines had been treated with P450-inducing or noninducing AEDs, or with prednisolone, applied to prevent oedema formation prior to neurosurgical resection of the epileptic hippocampus. Human patient samples were analyzed by immunohistochemical approach, the HN25.1 cell line by quantitative RT-PCR, CAT reporter gene assay, and immunoblot.


RESULTS
In both, humans and cell lines, the expression of testosterone metabolising CYP3A4 (human) or CYP3A11 (mouse) and AR was up-regulated when P450-inducing AEDs and/or prednisolone had been applied. AR responsive CAT reporter gene assay indicated an increase of AR-signalling after treatment of the HN25.1 cells with the P450-inducers phenytoin and carbamazepine. ERalpha expression was increased only by the P450-inducing AEDs, but not by prednisolone, which indicates that pathways different from CYP3A4/11 led to ERalpha enhancement.


CONCLUSIONS
We conclude that P450-inducing AEDs influence AR expression and signalling in hippocampus most likely via CYP3A4/11-induction. The HN25.1 cell line holds promise to investigate the correlation between drug application and AR regulation, and to specifically address issues that are relevant to human TLE patients.
Killer
Nina
N
Pathologisches Institut, Abteilung Neuropathologie, Neurozentrum, Freiburg, Germany.
Hock
Monika
M
Gehlhaus
Marcel
M
Capetian
Philipp
P
Knoth
Rolf
R
Pantazis
Georgios
G
Volk
Benedikt
B
Meyer
Ralf P
RP
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D002461:Cell Line, Transformed; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D012737:Sex Factors; D013256:Steroids / Q000494:pharmacology* / Q000627:therapeutic use
C410798:AR protein, human; D000927:Anticonvulsants; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D013256:Steroids; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A