DETECTION OF P450C17-INDEPENDENT PATHWAYS FOR DEHYDROEPIANDROSTERONE (DHEA) BIOSYNTHESIS IN BRAIN GLIAL TUMOR-CELLS

Dehydroepiandrosterone (D) is biosynthesized in the brain by a pathway different from that existing in the adrenal cortex. C6 rat glioma tum or cells in culture biosynthesize both pregnenolone (P) and D. They po ssess the mRNA, protein, and side-chain cleavage activity of P450scc, On the other hand, P450c17 was not detected. Adding FeSO4 to C6 cells increased the synthesis of both P and D. Even in the presence of amino glutethimide, an inhibitor of P450scc, FeSO4 increased the synthesis o f both steroids, indicating that the Fe2+-sensitive process does not i nvolve P450scc. Likewise, the FeSO4-induced formation of D was not blo cked by the P450c17 inhibitor, SU-10603. These results suggest that th e FeSO4-induced synthesis of D as well as of P in C6 cells may be due to the fragmentation of in situ-formed tertiary hydroperoxides, It is likely, however, that the effect of the Fe2+ is not limited to this on e reaction, When exogenous P was added to C6 microsomes, along with Fe SO4, the amount of D formed was greater than control values, indicatin g that Fe2+ facilitated the conversion of P to D. Unlike the constitue nts that are converted by Fe2+ to P, the precursor of D in C6 cells is not soluble in a 1:1 mixture of ether and ethylacetate. Treatment of C6 cells with KI, NaBH4, or HIO4 resulted in an increase in D synthesi s, From this it seems clear that a precursor of the D produced in C6 c ells is a steroid where both C-17 and C-20 are oxygenated.