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

source extracted confidence: high 2026-04-09
#humans #brain #cholesterol-side-chain-cleavage-enzyme #cytochrome-p-450-cyp1a1 #cytochrome-p-450-cyp1b1

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

Lin et al., 2023 | J Biol Chem | Other

Citation

Lin Yiqi Christina, Cheung Garett, ... Papadopoulos Vassilios. Mitochondrial cytochrome P450 1B1 is involved in pregnenolone synthesis in human brain cells. J Biol Chem. 2023-Aug;299(8):105035. doi:10.1016/j.jbc.2023.105035

Abstract

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.

Key Findings

These data suggest that mitochondrial CYP1B1 is involved in pregnenolone synthesis in human glial cells.

Outcomes Measured

  • Requires manual extraction

Population

Field Value
Population See abstract
Sample Size See abstract
Age Range See abstract
Condition inflammation

MeSH Terms

  • Humans
  • Brain
  • Cholesterol Side-Chain Cleavage Enzyme
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP1B1
  • Hydroxycholesterols
  • Mitochondria
  • Neuroglia
  • Pregnenolone
  • RNA, Small Interfering
  • Steroids

Evidence Classification

  • Level: Other
  • Publication Types: Journal Article, Research Support, Non-U.S. Gov't
  • Vertical: pregnenolone

Provenance

Source extracted via PubMed E-utilities API on 2026-04-12