Differential effects of antiepileptic drugs on steroidogenesis in a human in vitro cell model.
OBJECTIVE
To better understand the interaction of antiepileptic drugs and production of sex hormones, possible effects of valproate (VPA), levetiracetam (LEV) and carbamazepine (CBZ) on steroidogenesis were investigated in the human adrenal carcinoma cell line H295R.


METHODS
H295R cells were exposed to different concentrations of VPA, LEV or CBZ for 48 h. Sex hormone concentrations and mRNA expression levels were analyzed via radioimmunoassay and quantitative real time (RT)-PCR, respectively.


RESULTS
In VPA-exposed cells estradiol levels decreased in a dose-dependent manner, while testosterone and progesterone levels were unaffected. Expression of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), steroidogenic acute regulatory protein (StAR), CYP11a, CYP17, CYP21, 3betaHSD2, 17betaHSD1 was downregulated and expression of CYP11beta2 was upregulated. No effect on sex hormone production was observed under influence of LEV or CBZ. Expression of StAR, CYP17, CYP19 and 3betaHSD2 was downregulated in LEV-exposed cells, and expression of HMGR, CYP11beta2 and CYP17 was downregulated in CBZ-exposed cells.


CONCLUSIONS
VPA exposure resulted in a decrease in estradiol levels and a general downregulation of expression of genes encoding for enzymes early in steroidogenesis. No consistent changes were seen with LEV or CBZ exposure.
Gustavsen
M W
MW
Division of Clinical Neuroscience, Department of Neurology, Rikshospitalet University Hospital, Oslo, Norway.
von Krogh
K
K
Taubøll
E
E
Zimmer
K E
KE
Dahl
E
E
Olsaker
I
I
Ropstad
E
E
Verhaegen
S
S
D000927:Anticonvulsants / Q000494:pharmacology*; D002220:Carbamazepine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D052244:Endocrine Disruptors / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D000077287:Levetiracetam; D010750:Phosphoproteins / Q000235:genetics; D010889:Piracetam / Q000031:analogs & derivatives / Q000494:pharmacology; D011374:Progesterone / Q000378:metabolism; D011863:Radioimmunoassay; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000235:genetics; D013256:Steroids / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology; D000098682:Steroidogenic Acute Regulatory Protein
D000927:Anticonvulsants; D052244:Endocrine Disruptors; D010750:Phosphoproteins; D013256:Steroids; D000098682:Steroidogenic Acute Regulatory Protein; D002220:Carbamazepine; D013739:Testosterone; D000077287:Levetiracetam; D011374:Progesterone; D004958:Estradiol; D014635:Valproic Acid; D006903:Hydroxymethylglutaryl CoA Reductases; D013250:Steroid Hydroxylases; D010889:Piracetam