MOLECULAR ASPECTS OF THE EFFECT OF VALPROIC ACID ON ADRENAL AND TESTICULAR STEROIDOGENESIS.

L. BRION, F. CORNEJO MACIEL, A. GOROSTIZAGA, E. J. PODESTÁ, C. PAZ.

Pinamar, Buenos Aires, Argentina

Congreso; XLI Reunión Anual Sociedad Argentina de Investigación Bioquímica y Biología Molecular.; 2005

Sociedad Argentina de Investigación Bioquímica y Biología Molecular

Treatment with valproic acid (VA), an antiepileptic drug, frequently alters ovaric steroidogenesis by an unknown mechanism. At the molecular level, VA inhibits the histone-deacetylases, increasing gene transcription. The objective of this work was to study in detail the action of VA on steroidogenesis, using two mouse cell lines: Y1 (adrenocortical cells) and MA-10 (Leydig cells). In both cellular types, 1-3 mM VA increases basal and 8Br-cAMP and 22R-OH-cholesterol stimulated progesterone (P4) production. The effect on basal activity indicates that VA increases the cholesterol transport to the inner mitochondrial membrane, rate limiting step of steroidogenesis. In addition, the data suggest that the drug stimulates the cholesterol conversion to pregnenolone (P5) catalyzed by P450scc. Although VA increases histone acetylation, it does not induce P450scc gene expression, evaluated by Northern blot, suggesting that VA activates the enzyme. Another target of VA is the 3b-OH steroid dehydrogenase, enzyme that converts P5 into P4. The fact that the inhibition of this enzyme by VA does not affect cholesterol conversion into P4 suggests that the remaining enzyme activity is enough for steroid synthesis. These results indicate that besides the ovary, other steroidogenic tissues could be target of VA and they show that not all AV effects are mediated by the inhibition of histone-deacetylation, since it also affects enzyme activities.