Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017α and P450 aromatase localized in neurons

Yasushi Hojo, Taka Aki Hattori, Taihei Enami, Aizo Furukawa, Kumiko Suzuki, Hiro Taka Ishii, Hideo Mukai, John Morrison, William G M Janssen, Shiro Kominami, Nobuhiro Harada, Tetsuya Kimoto, Suguru Kawato

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)865-870
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number3
DOIs
StatePublished - Jan 20 2004
Externally publishedYes

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Pregnenolone
Aromatase
Cytochrome P-450 Enzyme System
Estradiol
Hippocampus
Neurons
Dehydroepiandrosterone
Cytochromes
Cholesterol
Pyramidal Cells
Oligodendroglia
Dentate Gyrus
N-Methylaspartate
Astrocytes
Endoplasmic Reticulum
Testosterone
Glutamic Acid
Electron Microscopy
Western Blotting
Steroids

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017α and P450 aromatase localized in neurons. / Hojo, Yasushi; Hattori, Taka Aki; Enami, Taihei; Furukawa, Aizo; Suzuki, Kumiko; Ishii, Hiro Taka; Mukai, Hideo; Morrison, John; Janssen, William G M; Kominami, Shiro; Harada, Nobuhiro; Kimoto, Tetsuya; Kawato, Suguru.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 3, 20.01.2004, p. 865-870.

Research output: Contribution to journalArticle

Hojo, Y, Hattori, TA, Enami, T, Furukawa, A, Suzuki, K, Ishii, HT, Mukai, H, Morrison, J, Janssen, WGM, Kominami, S, Harada, N, Kimoto, T & Kawato, S 2004, 'Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017α and P450 aromatase localized in neurons', Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 3, pp. 865-870. https://doi.org/10.1073/pnas.2630225100
Hojo, Yasushi ; Hattori, Taka Aki ; Enami, Taihei ; Furukawa, Aizo ; Suzuki, Kumiko ; Ishii, Hiro Taka ; Mukai, Hideo ; Morrison, John ; Janssen, William G M ; Kominami, Shiro ; Harada, Nobuhiro ; Kimoto, Tetsuya ; Kawato, Suguru. / Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017α and P450 aromatase localized in neurons. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 3. pp. 865-870.
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T1 - Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017α and P450 aromatase localized in neurons

AU - Hojo, Yasushi

AU - Hattori, Taka Aki

AU - Enami, Taihei

AU - Furukawa, Aizo

AU - Suzuki, Kumiko

AU - Ishii, Hiro Taka

AU - Mukai, Hideo

AU - Morrison, John

AU - Janssen, William G M

AU - Kominami, Shiro

AU - Harada, Nobuhiro

AU - Kimoto, Tetsuya

AU - Kawato, Suguru

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N2 - 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.

AB - 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.

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