Inhibitors of 7-Dehydrocholesterol Reductase: Screening of a Collection of Pharmacologically Active Compounds in Neuro2a Cells
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A small library of pharmacologically active compounds (the NIH Clinical Collection) was assayed in Neuro2a cells to determine their effect on the last step in the biosynthesis of cholesterol, the transformation of 7-dehydrocholesterol (7-DHC) to cholesterol promoted by 7-dehydrocholesterol reductase, DHCR7. Of some 727 compounds in the NIH Clinical Collection, over 30 compounds significantly increased 7-DHC in Neuro2a cells when assayed at 1 μM. Active compounds that increased 7-DHC with a Z-score of +3 or greater generally gave rise to modest decreases in desmosterol and increases in lanosterol levels. Among the most active compounds identified in the library were the antipsychotic, antidepressant, and anxiolytic compounds that included perospirone, nefazodone, haloperidol, aripiprazole, trazodone, and buspirone. Fluoxetine and risperidone were also active at 1 μM, and another 10 compounds in this class of pharmaceuticals were identified in the screen at concentrations of 10 μM. Increased levels of 7-DHC are associated with Smith-Lemli-Opitz syndrome (SLOS), a human condition that results from a mutation in the gene that encodes DHCR7. The SLOS phenotype includes neurological deficits and congenital malformations, and it is linked to a higher incidence of autism spectrum disorder. The significance of the current study is that it identifies common pharmacological compounds that may induce a biochemical presentation similar to SLOS. Little is known about the side effects of elevated 7-DHC postdevelopmentally, and the elevated 7-DHC that results from exposure to these compounds may also be a confounder in the diagnosis of SLOS.
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Trazodone and buspirone are known to increase 7DHC levels in individuals without SLOS.
“At the time of medical history completion, 2 years after AGRE obtained the blood sample, that subject was treated with trazodone and buspirone medications, which are known to increase 7DHC levels in individuals without SLOS [84, 85].”
From Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits (2021) · cites this paper as [85]
The Introduction reports elevated plasma 7-DHC in patients with false-positive SLOS diagnoses who were prescribed trazodone. The Abstract identifies both trazodone and buspirone as increasing 7-DHC in Neuro2a cells, but the paper does not establish that buspirone increases 7-DHC in people without SLOS. (LLM, conf=0.88)
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- Authors
- Kim, H.-Y. H., Korade, Z., Tallman, K. A., Liu, W., Weaver, C. D., Mirnics, K., & Porter, N. A.
- Affiliations
- Vanderbilt University (US)
- Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee 37235, United States
- Corresponding author
- Porter, Ned A.
- Venue
- Chemical Research in Toxicology
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-04-28
- Volume
- 29
- Issue
- 5
- Pages
- 892-900
- ISSN
- 0893-228X (ISSN-L)
- 1520-5010
- PMC
- PMC4868769
- OpenAlex
- W2337239988
- Cited by
- 53
- References
- 54
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 7 · 2023: 1 · 2022: 4 · 2021: 10 · 2020: 5 · 2019: 4 · 2018: 4 · 2017: 6 · 2015: 1
- FWCI
- 5.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Chemical Research in Toxicology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Environmental Health Sciences (R01 ES024133, R21 ES024666)
- National Institute of Neurological Disorders and Stroke
- National Institute of Child Health and Human Development (HD064727)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- DHCR7, 7-dehydrocholesterol, cholesterol biosynthesis, Smith-Lemli-Opitz syndrome, antipsychotic drugs, antidepressants, anxiolytics, N2a cells, desmosterol, lanosterol, autism spectrum disorder, drug screening
- MeSH terms
- Cell Line, Drug Evaluation, Preclinical, Humans, Oxidoreductases Acting on CH-CH Group Donors
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