The anti-epileptic drug valproic acid (VPA) inhibits steroidogenesis in bovine theca and granulosa cells in vitro.
The anti-epileptic drug valproic acid (VPA) inhibits steroidogenesis in bovine theca and granulosa cells in vitro.
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DOI：
10.1371/journal.pone.0049553
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Knight PG
中科院分区：
文献类型：
--
作者：
Glister C;Satchell L;Michael AE;Bicknell AB;Knight PG
丙戊酸(VPA)广泛用于治疗癫痫和双相情感障碍。据报道，接受VPA治疗的妇女多囊卵巢综合征(PCOS)样症状的发生率增加，包括高雄激素血症和少经或闭经。为了研究VPA对卵巢类固醇合成的潜在直接影响，我们使用了原代牛卵泡膜(TC)和颗粒(GC)细胞，这些细胞保持在保留其‘卵泡’表型的条件下。测定VPA(7.8~500µg/ml)对TC的影响。用FSH或IGF类似物检测VPA对GC的影响。丙戊酸抑制(P<；0.0001)基础(70%抑制；IC_(50)67±10微克/毫升)和黄体生成素(93%抑制；IC_(50)58±10微克/毫升)。VPA使细胞色素P17A1mRNA丰度降低99%(P<0.0001)，对LHR、STAR、Cyp11a1和HSD3B1mRNA影响较小(P<0.05)。VPA只减少黄体生成素最高剂量所诱导的TC孕酮分泌，而Tc值不受VPA影响。在较高浓度(125-500微克/毫升)，丙戊酸抑制基础、促卵泡刺激素和胰岛素样生长因子刺激的雌二醇分泌(P<；0.0001)，而不影响孕酮的分泌和细胞数量。丙戊酸逆转促卵泡刺激素诱导的细胞色素P19A1和HSD17B1mRNA表达上调(P<；0.001)。强效的组蛋白脱乙酰酶(HDAC)抑制剂曲古菌素A和斯替普泰也抑制TC雄烯二酮的分泌和颗粒细胞雌激素的分泌，提示VPA的作用反映了其对HDAC的抑制作用。总而言之，这些发现驳斥了VPA对TC雄激素输出有直接刺激作用的假设。相反，VPA抑制依赖于黄体生成素的雄激素的产生和依赖于卵泡刺激素/胰岛素样生长因子的雌二醇的产生，这可能是通过抑制HDAC来实现的。
Valproic acid (VPA) is used widely to treat epilepsy and bipolar disorder. Women undergoing VPA treatment reportedly have an increased incidence of polycystic ovarian syndrome (PCOS)-like symptoms including hyperandrogenism and oligo- or amenorrhoea. To investigate potential direct effects of VPA on ovarian steroidogenesis we used primary bovine theca (TC) and granulosa (GC) cells maintained under conditions that preserve their ‘follicular’ phenotype. Effects of VPA (7.8–500 µg/ml) on TC were tested with/without LH. Effects of VPA on GC were tested with/without FSH or IGF analogue. VPA reduced (P<0.0001) both basal (70% suppression; IC50 67±10 µg/ml) and LH-induced (93% suppression; IC50 58±10 µg/ml) androstenedione secretion by TC. VPA reduced CYP17A1 mRNA abundance (>99% decrease; P<0.0001) with lesser effects on LHR, STAR, CYP11A1 and HSD3B1 mRNA (<90% decrease; P<0.05). VPA only reduced TC progesterone secretion induced by the highest (luteinizing) LH dose tested; TC number was unaffected by VPA. At higher concentrations (125–500 µg/ml) VPA inhibited basal, FSH- and IGF-stimulated estradiol secretion (P<0.0001) by GC without affecting progesterone secretion or cell number. VPA reversed FSH-induced upregulation of CYP19A1 and HSD17B1 mRNA abundance (P<0.001). The potent histone deacetylase (HDAC) inhibitors trichostatin A and scriptaid also suppressed TC androstenedione secretion and granulosal cell oestrogen secretion suggesting that the action of VPA reflects its HDAC inhibitory properties. In conclusion, these findings refute the hypothesis that VPA has a direct stimulatory action on TC androgen output. On the contrary, VPA inhibits both LH-dependent androgen production and FSH/IGF-dependent estradiol production in this in vitro bovine model, likely by inhibition of HDAC.
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