Cascio C, Prasad V V, Lin Y Y, Lieberman S, Papadopoulos V
Department of Cell Biology, Georgetown University Medical Center, Washington, DC 20007, USA.
Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2862-7. doi: 10.1073/pnas.95.6.2862.
Dehydroepiandrosterone (D) is biosynthesized in the brain by a pathway different from that existing in the adrenal cortex. C6 rat glioma tumor cells in culture biosynthesize both pregnenolone (P) and D. They possess 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 aminoglutethimide, an inhibitor of P450scc, FeSO4 increased the synthesis of both steroids, indicating that the Fe2+-sensitive process does not involve P450scc. Likewise, the FeSO4-induced formation of D was not blocked by the P450c17 inhibitor, SU-10603. These results suggest that the 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 one reaction. When exogenous P was added to C6 microsomes, along with FeSO4, the amount of D formed was greater than control values, indicating that Fe2+ facilitated the conversion of P to D. Unlike the constituents 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 synthesis. From this it seems clear that a precursor of the D produced in C6 cells is a steroid where both C-17 and C-20 are oxygenated.
脱氢表雄酮（D）在大脑中的生物合成途径与肾上腺皮质中的不同。培养的C6大鼠胶质瘤肿瘤细胞能生物合成孕烯醇酮（P）和D。它们具有P450scc的mRNA、蛋白质和侧链裂解活性。另一方面，未检测到P450c17。向C6细胞中添加硫酸亚铁（FeSO4）可增加P和D的合成。即使存在P450scc抑制剂氨鲁米特，FeSO4仍能增加两种类固醇的合成，这表明Fe2+敏感过程不涉及P450scc。同样，P450c17抑制剂SU-10603也不能阻断FeSO4诱导的D形成。这些结果表明，FeSO4诱导C6细胞中D以及P的合成可能是由于原位形成的叔氢过氧化物的裂解。然而，Fe2+的作用可能不限于这一反应。当向C6微粒体中添加外源性P并同时加入FeSO4时，形成的D量大于对照值，表明Fe2+促进了P向D的转化。与被Fe2+转化为P的成分不同，C6细胞中D的前体不溶于乙醚和乙酸乙酯的1:1混合物。用碘化钾（KI）、硼氢化钠（NaBH4）或高碘酸（HIO4）处理C6细胞会导致D合成增加。由此看来很明显，C6细胞中产生的D的前体是一种C-17和C-20都被氧化的类固醇。
