VALPROIC ACID AFFECTS ADRENAL AND TESTICULAR STEROIDOGENESESIS BY A MECHANISM INDEPENDENT OF ITS ACTION ON HISTONE-DEACETYLASES.

L. BRION; F. CORNEJO MACIEL; A. GOROSTIZAGA; G. SUÁREZ; E.J. PODESTÁ; C. PAZ

Boston, Massachussets. USA.

Conferencia; XII th Adrenal Cortex and Vth Molecular Steroidogenesis Conference; 2006

Bernard Shimmer and Alexander Brownie, members of the Organizing Commitee

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. Here we analyzed the effect of this compound on steroidogenesis, using adrenocortical (Yl) and Leydig (MA-10) cells. In both cellular types, 1-3 mM VA increases basal, 8Br-cAMP and 22R-OH-cholesterol (22R) stimulated progesterone (P4) production. The effect on basal activity indicates that VA increases cholesterol transport to the inner mitochondrial membrane, however it does not affect StAR induction. The effect on 22R suggests an action on the expression and/or activity of P450scc (SCC). Even when V A increases histone acetylation, it does not induce SCC gene expression, suggesting a stimulatory action on the enzyme. In vitro assays demonstrate that VA inhibits the 3Beta-0H steroid dehydrogenase (HSD), in accordance with the fact that it also inhibits the conversion of pregnenolone into P4. Our study indicates that besides the ovary, other steroidogenic tissues could be target of VA and that not all its effects are mediated by the inhibition of histone-deacetylases. The drug increases cholesterol accessibility to SCC and affects the activities of SCC and HSD, being fue stimulatory effect on SCC enough to mask fue action on HSD when cholesterol conversion to P4 is measured.