Valproate potentiates androgen biosynthesis in human ovarian theca cells.

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Nelson-DeGrave VL, Wickenheisser JK, Cockrell JE, Wood JR, Legro RS, Strauss JF 3rd, McAllister JM

Valproate potentiates androgen biosynthesis in human ovarian theca cells.

Endocrinology. 2004 Feb;145(2):799-808. Epub 2003 Oct 23.

PubMed ID

14576182 [ View in PubMed

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Abstract

In patients with epilepsy, treatment with valproate (VPA) has been reported to be associated with polycystic ovary syndrome-like symptoms including weight gain, hyperandrogenemia, and hyperinsulinemia. We examined the effect of VPA on androgen biosynthesis in ovarian theca cells isolated from follicles of normal cycling women to determine whether the hyperandrogenemia reported with VPA treatment could be a result of direct effects of VPA on the ovary. In long-term cultures of theca cells treated for 72 h with sodium valproate (30-3000 microm), we observed an increase in basal and forskolin-stimulated dehydroepiandrosterone (DHEA), androstenedione, and 17alpha-hydroxyprogesterone production compared with control values. In contrast, low doses of VPA treatment (i.e. 30-300 microm) had no effect on basal and forskolin-stimulated progesterone production, whereas higher doses of VPA (1000-3000 microm) inhibited progesterone production. The most pronounced effect of VPA on androgen biosynthesis was observed in the dose range of 300-3000 microm, which represent therapeutic levels in the treatment of epilepsy and bipolar disorder. Western analyses demonstrated that VPA treatment increased both basal and forskolin-stimulated P450c17 and P450scc protein levels, whereas the amount of steroidogenic acute regulatory protein was unaffected. In transient transfection studies, VPA was found to increase P450 17alpha-hydroxylase and P450 cholesterol side-chain cleavage promoter activity, whereas steroidogenic acute regulatory protein promoter activity was unaffected. Consistent with the ability of VPA to act as a histone deacetylase (HDAC) inhibitor in other cell systems, VPA (500 microm) treatment was observed to increase histone H3 acetylation and P450 17alpha-hydroxylase mRNA accumulation. The HDAC inhibitor butyric acid (500 microm) similarly increased histone H3 acetylation and DHEA biosynthesis, whereas the VPA derivative valpromide (500 microm), which lacks HDAC inhibitory activity, had no effect on histone acetylation or DHEA biosynthesis. These data suggest that VPA-induced ovarian androgen biosynthesis results from changes in chromatin modifications (histone acetylation) that augment transcription of steroidogenic genes. These studies provide the first biochemical evidence to support a role for VPA in the genesis of polycystic ovary syndrome-like symptoms, and establish a direct link between VPA treatment and increased ovarian androgen biosynthesis.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Valproic acid	Histone deacetylase (Protein Group)	Protein group	Humans	Unknown	Inhibitor	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Valproic acid	Approved Investigational	CYP11A1	1583	upregulated	Valproic Acid results in increased expression of CYP11A1 mRNA	15q24.1
Valproic acid	Approved Investigational	CYP17A1	1586	upregulated	Valproic Acid results in increased expression of CYP17A1 mRNA	10q24.32