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Mitochondrial cytochrome P450 1B1 is involved in pregnenolone synthesis in human brain cells

Neurosteroids, which are steroids synthesized by the nervous system, can exert neuromodulatory and neuroprotective effects via genomic and nongenomic pathways. The neurosteroid and major steroid precursor pregnenolone has therapeutical potential in various diseases, such as psychiatric and pain diso...

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Autores principales: Lin, Yiqi Christina, Cheung, Garett, Zhang, Zeyu, Papadopoulos, Vassilios
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10413356/
https://www.ncbi.nlm.nih.gov/pubmed/37442234
http://dx.doi.org/10.1016/j.jbc.2023.105035
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author Lin, Yiqi Christina
Cheung, Garett
Zhang, Zeyu
Papadopoulos, Vassilios
author_facet Lin, Yiqi Christina
Cheung, Garett
Zhang, Zeyu
Papadopoulos, Vassilios
author_sort Lin, Yiqi Christina
collection PubMed
description Neurosteroids, which are steroids synthesized by the nervous system, can exert neuromodulatory and neuroprotective effects via genomic and nongenomic pathways. The neurosteroid and major steroid precursor pregnenolone has therapeutical potential in various diseases, such as psychiatric and pain disorders, and may play important roles in myelination, neuroinflammation, neurotransmission, and neuroplasticity. Although pregnenolone is synthesized by CYP11A1 in peripheral steroidogenic organs, our recent study showed that pregnenolone must be synthesized by another mitochondrial cytochrome P450 (CYP450) enzyme other than CYP11A1 in human glial cells. Therefore, we sought to identify the CYP450 responsible for pregnenolone production in the human brain. Upon screening for CYP450s expressed in the human brain that have mitochondrial localization, we identified three enzyme candidates: CYP27A1, CYP1A1, and CYP1B1. We found that inhibition of CYP27A1 through inhibitors and siRNA knockdown did not negatively affect pregnenolone synthesis in human glial cells. Meanwhile, treatment of human glial cells with CYP1A1/CYP1B1 inhibitors significantly reduced pregnenolone production in the presence of 22(R)-hydroxycholesterol. We performed siRNA knockdown of CYP1A1 or CYP1B1 in human glial cells and found that only CYP1B1 knockdown significantly decreased pregnenolone production. Furthermore, overexpression of mitochondria-targeted CYP1B1 significantly increased pregnenolone production under basal conditions and in the presence of hydroxycholesterols and low-density lipoprotein. Inhibition of CYP1A1 and/or CYP1B1 via inhibitors or siRNA knockdown did not significantly reduce pregnenolone synthesis in human adrenal cortical cells, implying that CYP1B1 is not a major pregnenolone-producing enzyme in the periphery. These data suggest that mitochondrial CYP1B1 is involved in pregnenolone synthesis in human glial cells.
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spelling pubmed-104133562023-08-11 Mitochondrial cytochrome P450 1B1 is involved in pregnenolone synthesis in human brain cells Lin, Yiqi Christina Cheung, Garett Zhang, Zeyu Papadopoulos, Vassilios J Biol Chem Research Article Neurosteroids, which are steroids synthesized by the nervous system, can exert neuromodulatory and neuroprotective effects via genomic and nongenomic pathways. The neurosteroid and major steroid precursor pregnenolone has therapeutical potential in various diseases, such as psychiatric and pain disorders, and may play important roles in myelination, neuroinflammation, neurotransmission, and neuroplasticity. Although pregnenolone is synthesized by CYP11A1 in peripheral steroidogenic organs, our recent study showed that pregnenolone must be synthesized by another mitochondrial cytochrome P450 (CYP450) enzyme other than CYP11A1 in human glial cells. Therefore, we sought to identify the CYP450 responsible for pregnenolone production in the human brain. Upon screening for CYP450s expressed in the human brain that have mitochondrial localization, we identified three enzyme candidates: CYP27A1, CYP1A1, and CYP1B1. We found that inhibition of CYP27A1 through inhibitors and siRNA knockdown did not negatively affect pregnenolone synthesis in human glial cells. Meanwhile, treatment of human glial cells with CYP1A1/CYP1B1 inhibitors significantly reduced pregnenolone production in the presence of 22(R)-hydroxycholesterol. We performed siRNA knockdown of CYP1A1 or CYP1B1 in human glial cells and found that only CYP1B1 knockdown significantly decreased pregnenolone production. Furthermore, overexpression of mitochondria-targeted CYP1B1 significantly increased pregnenolone production under basal conditions and in the presence of hydroxycholesterols and low-density lipoprotein. Inhibition of CYP1A1 and/or CYP1B1 via inhibitors or siRNA knockdown did not significantly reduce pregnenolone synthesis in human adrenal cortical cells, implying that CYP1B1 is not a major pregnenolone-producing enzyme in the periphery. These data suggest that mitochondrial CYP1B1 is involved in pregnenolone synthesis in human glial cells. American Society for Biochemistry and Molecular Biology 2023-07-11 /pmc/articles/PMC10413356/ /pubmed/37442234 http://dx.doi.org/10.1016/j.jbc.2023.105035 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Lin, Yiqi Christina
Cheung, Garett
Zhang, Zeyu
Papadopoulos, Vassilios
Mitochondrial cytochrome P450 1B1 is involved in pregnenolone synthesis in human brain cells
title Mitochondrial cytochrome P450 1B1 is involved in pregnenolone synthesis in human brain cells
title_full Mitochondrial cytochrome P450 1B1 is involved in pregnenolone synthesis in human brain cells
title_fullStr Mitochondrial cytochrome P450 1B1 is involved in pregnenolone synthesis in human brain cells
title_full_unstemmed Mitochondrial cytochrome P450 1B1 is involved in pregnenolone synthesis in human brain cells
title_short Mitochondrial cytochrome P450 1B1 is involved in pregnenolone synthesis in human brain cells
title_sort mitochondrial cytochrome p450 1b1 is involved in pregnenolone synthesis in human brain cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10413356/
https://www.ncbi.nlm.nih.gov/pubmed/37442234
http://dx.doi.org/10.1016/j.jbc.2023.105035
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