Adult Male Rat Hippocampus Synthesizes Estradiol from Pregnenolone by Cytochromes P45017α and P450 Aromatase Localized in Neurons

In adult mammalian brain, occurrence of the synthesis of estradiol from endogenous cholesterol has been doubted because of the inability to detect dehydroepiandrosterone synthase, P45017α. In adult male rat hippocampal formation, significant localization was demonstrated for both cytochromes P45017α...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2004-01, Vol.101 (3), p.865-870
Main Authors: Hojo, Yasushi, Hattori, Taka-aki, Enami, Taihei, Furukawa, Aizo, Suzuki, Kumiko, Ishii, Hiro-taka, Mukai, Hideo, Morrison, John H., William G. M. Janssen, Kominami, Shiro, Harada, Nobuhiro, Kimoto, Tetsuya, Kawato, Suguru
Format: Article
Language:English
Subjects:
Biological Sciences
Brain
Cytochromes
Hippocampus
Messenger RNA
Neuroglia
Neurons
Pyramidal cells
Solvents
Steroids
Testosterone
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Summary:In adult mammalian brain, occurrence of the synthesis of estradiol from endogenous cholesterol has been doubted because of the inability to detect dehydroepiandrosterone synthase, P45017α. In adult male rat hippocampal formation, significant localization was demonstrated for both cytochromes P45017α and P450 aromatase, in pyramidal neurons in the CA1-CA3 regions, as well as in the granule cells in the dentate gyrus, by means of immunohistochemical staining of slices. Only a weak immunoreaction of these P450s was observed in astrocytes and oligodendrocytes. ImmunoGold electron microscopy revealed that P45017α and P450 aromatase were localized in pre- and postsynaptic compartments as well as in the endoplasmic reticulum in principal neurons. The expression of these cytochromes was further verified by using Western blot analysis and RT-PCR. Stimulation of hippocampal neurons with N-methyl-D-aspartate induced a significant net production of estradiol. Analysis of radioactive metabolites demonstrated the conversion from [3H]pregnenolone to [3H]estradiol through dehydroepiandrosterone and testosterone. This activity was abolished by the application of specific inhibitors of cytochrome P450s. Interestingly, estradiol was not significantly converted to other steroid metabolites. Taken together with our previous finding of a P450scc-containing neuronal system for pregnenolone synthesis, these results imply that 17β-estradiol is synthesized by P45017α and P450 aromatase localized in hippocampal neurons from endogenous cholesterol. This synthesis may be regulated by a glutamate-mediated synaptic communication that evokes Ca2+signals.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2630225100