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Medication effects on developmental sterol biosynthesis.

Zeljka Korade1,2, Marija Heffer3, Károly Mirnics4,5

  • 1Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, 68198, USA.

Molecular Psychiatry
|April 6, 2021
PubMed
Summary
This summary is machine-generated.

Common medications can disrupt brain development by interfering with cholesterol synthesis. DHCR7 inhibitors, particularly when combined with genetic mutations, pose risks to fetal brain development, highlighting the need for personalized medicine.

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Area of Science:

  • Neuroscience
  • Genetics
  • Pharmacology

Background:

  • Cholesterol is vital for brain function and development.
  • Genetic defects in sterol biosynthesis cause intellectual and developmental disabilities.
  • Developing neurons synthesize cholesterol; this process can be disrupted by genetic and chemical factors.

Purpose of the Study:

  • To investigate the impact of medications interfering with sterol biosynthesis on fetal brain development.
  • To examine the role of dehydrocholesterol-reductase 7 (DHCR7) inhibition and its consequences.
  • To explore gene-medication interactions in the context of cholesterol biosynthesis.

Main Methods:

  • Analysis of medications known to interfere with sterol biosynthesis.
  • Investigation of dehydrocholesterol-reductase 7 (DHCR7) enzyme function.
  • Utilized a mouse model with Dhcr7+/- genotype and studied human dermal fibroblasts with DCHR7+/- mutations.

Main Results:

  • Inhibition of DHCR7 leads to the accumulation of toxic 7-dehydrocholesterol (7-DHC).
  • A gene-medication interaction exacerbates developmental brain toxicity in a mouse model.
  • Evidence suggests this interaction occurs in humans, with implications for pregnant women using these medications.

Conclusions:

  • DHCR7 inhibitors used during pregnancy may act as teratogens, posing risks to fetal brain development.
  • Medications inhibiting sterol biosynthesis require cautious use in individuals with sterol biosynthesis gene mutations.
  • Precision medicine approaches, considering patient genotype and life stage, are crucial for improving fetal and infant safety.