TY - JOUR
T1 - Medication effects on developmental sterol biosynthesis
AU - Korade, Zeljka
AU - Heffer, Marija
AU - Mirnics, Károly
N1 - Funding Information:
We are very grateful to Dr. Matthew Sandbulte for edits and invaluable comments on the manuscript. We also want to thank all Mirnics, Korade (UNMC) and Ned A. Porter lab members (Vanderbilt University) for their hard work and dedications to our projects. Finally, we greatly appreciate the generosity of all patients and families who contributed the biomaterials for the above-described studies. Multiple reported studies in this review have been funded by The National Institutes of Health, NICHD HD064727 (NAP), NIMH MH110636 (KM, NAP), NIEHS ES024133 (NAP, ZK) and NIMH MH067234 (KM).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/1
Y1 - 2022/1
N2 - Cholesterol is essential for normal brain function and development. Genetic disruptions of sterol biosynthesis result in intellectual and developmental disabilities. Developing neurons synthesize their own cholesterol, and disruption of this process can occur by both genetic and chemical mechanisms. Many commonly prescribed medications interfere with sterol biosynthesis, including haloperidol, aripiprazole, cariprazine, fluoxetine, trazodone and amiodarone. When used during pregnancy, these compounds might have detrimental effects on the developing brain of the offspring. In particular, inhibition of dehydrocholesterol-reductase 7 (DHCR7), the last enzyme in the biosynthesis pathway, results in accumulation of the immediate cholesterol precursor, 7-dehydrocholesterol (7-DHC). 7-DHC is highly unstable, giving rise to toxic oxysterols; this is particularly pronounced in a mouse model when both the mother and the offspring carry the Dhcr7+/- genotype. Studies of human dermal fibroblasts from individuals who carry DCHR7+/- single allele mutations suggest that the same gene*medication interaction also occurs in humans. The public health relevance of these findings is high, as DHCR7-inhibitors can be considered teratogens, and are commonly used by pregnant women. In addition, sterol biosynthesis inhibiting medications should be used with caution in individuals with mutations in sterol biosynthesis genes. In an age of precision medicine, further research in this area could open opportunities to improve patient and fetal/infant safety by tailoring medication prescriptions according to patient genotype and life stage.
AB - Cholesterol is essential for normal brain function and development. Genetic disruptions of sterol biosynthesis result in intellectual and developmental disabilities. Developing neurons synthesize their own cholesterol, and disruption of this process can occur by both genetic and chemical mechanisms. Many commonly prescribed medications interfere with sterol biosynthesis, including haloperidol, aripiprazole, cariprazine, fluoxetine, trazodone and amiodarone. When used during pregnancy, these compounds might have detrimental effects on the developing brain of the offspring. In particular, inhibition of dehydrocholesterol-reductase 7 (DHCR7), the last enzyme in the biosynthesis pathway, results in accumulation of the immediate cholesterol precursor, 7-dehydrocholesterol (7-DHC). 7-DHC is highly unstable, giving rise to toxic oxysterols; this is particularly pronounced in a mouse model when both the mother and the offspring carry the Dhcr7+/- genotype. Studies of human dermal fibroblasts from individuals who carry DCHR7+/- single allele mutations suggest that the same gene*medication interaction also occurs in humans. The public health relevance of these findings is high, as DHCR7-inhibitors can be considered teratogens, and are commonly used by pregnant women. In addition, sterol biosynthesis inhibiting medications should be used with caution in individuals with mutations in sterol biosynthesis genes. In an age of precision medicine, further research in this area could open opportunities to improve patient and fetal/infant safety by tailoring medication prescriptions according to patient genotype and life stage.
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U2 - 10.1038/s41380-021-01074-5
DO - 10.1038/s41380-021-01074-5
M3 - Review article
C2 - 33820938
AN - SCOPUS:85103616676
SN - 1359-4184
VL - 27
SP - 490
EP - 501
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 1
ER -