Medication effects on developmental sterol biosynthesis.

Autor: Korade Z; Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA., Heffer M; J. J. Strossmayer University of Osijek, Faculty of Medicine Osijek, Department of Medical Biology and Genetics, Josipa Huttlera 4, 31000, Osijek, Croatia., Mirnics K; Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA. karoly.mirnics@unmc.edu.; Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, 68105, USA. karoly.mirnics@unmc.edu.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2022 Jan; Vol. 27 (1), pp. 490-501. Date of Electronic Publication: 2021 Apr 05.
DOI: 10.1038/s41380-021-01074-5
Abstrakt: 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.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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