RRC ID 39825
Author Brown RC, Cascio C, Papadopoulos V.
Title Pathways of neurosteroid biosynthesis in cell lines from human brain: regulation of dehydroepiandrosterone formation by oxidative stress and beta-amyloid peptide.
Journal J. Neurochem.
Abstract Neurosteroids in rodents can originate from peripheral tissues or be locally synthesized in specific brain areas. There is, as yet, no information about the synthesis and regulation of neurosteroids in human brain. We examined the ability of human brain cells to synthesize steroids from a radiolabeled precursor and the mRNA and protein expression of key components of peripheral steroidogenic machinery. Oligodendrocytes are the source of pregnenolone in human brain. Human astrocytes do not synthesize radiolabeled pregnenolone, nor do human neurons. There is potential for all three cell types to metabolize pregnenolone to other neurosteroids, including dehydroepiandrosterone. mRNA and protein for cytochrome P450 17alpha-hydroxylase were found in all cell types, although no activity could be demonstrated. We examined the ability of the cells to make dehydroepiandrosterone via an alternative pathway induced by treatment with Fe2+. Oligodendrocytes and astrocytes make dehydroepiandrosterone via this pathway, but neurons do not. In searching for a natural regulator of dehydroepiandrosterone formation, we observed that treating oligodendrocytes with beta-amyloid, which increases reactive oxygen species, also increased dehydroepiandrosterone formation. These effects of beta-amyloid were blocked by vitamin E. These results indicate that human brain makes steroids in a cell-specific manner and suggest that dehydroepiandrosterone synthesis can be regulated by intracellular free radicals.
Volume 74(2)
Pages 847-59
Published 2000-2
DOI 10.1046/j.1471-4159.2000.740847.x
PMID 10646538
MeSH 3-Hydroxysteroid Dehydrogenases / genetics 3-Hydroxysteroid Dehydrogenases / metabolism Amyloid beta-Peptides / physiology Astrocytes / metabolism Brain / cytology Brain / metabolism* Cholesterol Side-Chain Cleavage Enzyme / genetics Cholesterol Side-Chain Cleavage Enzyme / metabolism Dehydroepiandrosterone / biosynthesis* Ferrous Compounds / pharmacology Humans Intracellular Membranes / metabolism Neurons / metabolism Oligodendroglia / metabolism Oxidative Stress / physiology Pregnenolone / biosynthesis RNA, Messenger / metabolism Reactive Oxygen Species / metabolism Receptors, GABA-A / genetics Receptors, GABA-A / metabolism Steroid 17-alpha-Hydroxylase / genetics Steroid 17-alpha-Hydroxylase / metabolism Steroids / biosynthesis* Tumor Cells, Cultured
IF 4.87
Times Cited 80
WOS Category NEUROSCIENCES BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
Human and Animal Cells