Dehydroepiandrosterone: biosynthesis and metabolism in the brain

Dehydroepiandrosterone (DHEA) is abundantly found in brain tissues of several species, including human. However, the cellular origin and pathway by which DHEA is synthesized in brain are not yet known. We have, therefore, initiated pilot experiments to explore gene expression of cytochrome P450 17alpha-hydroxylase (P450c17), the key steroidogenic enzyme for androgen synthesis, and evaluate DHEA production by highly purified astrocytes, oligodendrocytes, and neurons. Using RT-PCR, we have demonstrated for the first time that astrocytes and neurons in the cerebral cortex of neonatal rat brain express P450c17. The presence of P450c17 in astrocytes and neurons was supported by the ability of these cells to metabolize pregnenolone to DHEA in a dose-dependent manner as determined by RIA. These data were further confirmed by production of androstenedione by astrocytes using progesterone as a substrate. However, cortical neurons express a low transcript of P450c17 messenger RNA and produce low levels of DHEA and androstenedione compared with astrocytes. Oligodendrocytes neither express the messenger RNA nor produce DHEA. The production of DHEA by astrocytes is not limited to cerebral cortex, as hypothalamic astrocytes produce DHEA at a level 3 times higher than that produced by cortical astrocytes. Cortical and hypothalamic astrocytes also have the capacity to metabolize DHEA to testosterone and estradiol in a dose-dependent manner. However, hypothalamic astrocytes were 3 times more active than cortical astrocytes in the metabolism of DHEA to estradiol. In conclusion, our data presented evidence that astrocytes and neurons express P450c17 and synthesize DHEA from pregnenolone. Astrocytes also have the capacity to metabolize DHEA into sex steroid hormones. These data suggest that as in gonads and adrenal, DHEA is biosynthesized in the brain by a P450c17-dependent mechanism.