Abstracts

RATIONALE: Several antiepileptic drugs (AEDs) affect sex steroid hormone levels. In women, hyperandrogenism has recently been described after long-term use of valproate while phenytoin reduces free estrogen levels. The underlying mechanisms behind these effects are still unclear. Displacement of estrogen from its receptor by antiepileptic drugs would contribute to a relative androgen dominance. The aim of this study was 1) to evaluate the affinity of valproate (VPA), phenobarbital (PB), phenytoin (PHT) or lamotrigine (LTG) to the estrogen receptor, and 2) to evaluate if any of the AEDs stimulated growth in the estrogen-dependent human breast cancer cell-line MCF-7.
METHODS: Binding affinity of AEDs to [alpha]estrogen receptors (ER) was studied by incubating ER isolated from MCF-7 cells with radiolabelled 17[beta]-estradiol in combination with unlabelled 17[beta]-estradiol or the different AEDs for 2 hours. Cell growth of MCF-7 cells was measured after 6 days in an estrogen-depleted medium with or without AEDs.
RESULTS: None of the AEDs studied showed affinity to the ER when tested in cytosolic cell-extracts. VPA, but none of the other AEDs, induced a slight increase in cell growth (19 [plusminus]11%, 100 [mu]M). This was abolished by the addition of the estrogen receptor antagonists ICI 182,780 (1 nM) or 4-hydroxy tamoxifen (100 nM).
CONCLUSIONS: None of the AEDs studied (VPA, PB, PHT, LTG) showed affinity to the estrogen receptor. VPA was able to induce cell growth at low therapeutic concentrations. The estrogen receptor seems to be involved since the effect was abolished by estrogen receptor antagonists. Since no binding to the estrogen receptor was observed, the induced cell growth could be a result of another signalling pathway cross-talking with the estrogen receptor pathway.