Pathways of dehydroepiandrosterone formation in rat brain glia

In peripheral steroidogenic tissues, dehydroepiandrosterone (D) is formed f rom pregnenolone (P) by the microsomal cytochrome P450c17 enzyme. Although some steroidogenic P450s have been found in brain tissue, no enzyme has bee n shown to possess P450c17 activity. We recently demonstrated the presence of an alternative. Fe2+-dependent pathway responsible for D formation from alternative precursors in rat glioma cells. We and others could not find P4 50c17 mRNA and protein in rat brain. but demonstrate herein the presence of Fe2+-dependent alternative pathway for D formation in rat brain cortex mic rosomes. Using primary cultures of differentiating rat glial cells, we obse rved that P450c17 mRNA and protein were present in O-2A oligodendrocyte pre cursors and mature oligodendrocytes. In the presence of P, O-2A and mature oligodendrocytes formed D. Addition of Fe2+ together with submaximal concen trations of P increased D formation by these cells. Treatment of oligodendr ocytes with the P450c17 inhibitor SU 10603 in the presence or absence of P failed to inhibit D production. These data suggest that D formation in olig odendrocytes occurs independently of the P450c17 protein present in the cel ls. In isolated type I astrocytes we did not find neither P450c17 mRNA nor protein. These cells responded to Fe2+ by producing D and addition of P tog ether with Fe2+ further increased D synthesis. SU 10603 failed to inhibit D formation by astrocytes. Taken together these results suggest that in diff erentiating rat brain oligodendrocytes and astrocytes D is formed via a F45 0c17-independent and oxidative stress-dependent alternative pathway. (C) 20 01 Elsevier Science Ltd. All rights reserved.