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J Lipid Res. 2017 Nov;58(11):2139-2146. doi: 10.1194/jlr.M079475. Epub 2017 Sep 28.

Vulnerability of DHCR7+/- mutation carriers to aripiprazole and trazodone exposure.

Author information

1
Departments of Pediatrics and Biochemistry and Molecular Biology University of Nebraska Medical Center, Omaha, NE 68198.
2
Department of Chemistry and Vanderbilt Institute of Chemical Biology Vanderbilt University, Nashville, TN 37235.
3
Department of Pharmacology, Vanderbilt University, Nashville, TN 37235.
4
Department of Laboratory Medicine, Division of Clinical Genetics, University of Debrecen, Debrecen 4032, Hungary.
5
Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE 68198.
6
Department of Chemistry and Vanderbilt Institute of Chemical Biology Vanderbilt University, Nashville, TN 37235 n.porter@vanderbilt.edu.

Abstract

Smith-Lemli-Opitz syndrome is a recessive disorder caused by mutations in 7-dehydrocholesterol reductase (DHCR)7 with a heterozygous (HET) carrier frequency of 1-3%. A defective DHCR7 causes accumulation of 7-dehydrocholesterol (DHC), which is a highly oxidizable and toxic compound. Recent studies suggest that several antipsychotics, including the highly prescribed pharmaceuticals, aripiprazole (ARI) and trazodone (TRZ), increase 7-DHC levels in vitro and in humans. Our investigation was designed to compare the effects of ARI and TRZ on cholesterol (Chol) synthesis in fibroblasts from DHCR7+/- human carriers and controls (CTRs). Six matched pairs of fibroblasts were treated and their sterol profile analyzed by LC-MS. Significantly, upon treatment with ARI and TRZ, the total accumulation of 7-DHC was higher in DHCR7-HET cells than in CTR fibroblasts. The same set of experiments was repeated in the presence of 13C-lanosterol to determine residual Chol synthesis, revealing that ARI and TRZ strongly inhibit de novo Chol biosynthesis. The results suggest that DHCR7 carriers have increased vulnerability to both ARI and TRZ exposure compared with CTRs. Thus, the 1-3% of the population who are DHCR7 carriers may be more likely to sustain deleterious health consequences on exposure to compounds like ARI and TRZ that increase levels of 7-DHC, especially during brain development.

KEYWORDS:

7-dehydrocholesterol; 7-dehydrocholesterol reductase; antipsychotics; fibroblasts

PMID:
28972118
PMCID:
PMC5665669
DOI:
10.1194/jlr.M079475
[Indexed for MEDLINE]
Free PMC Article

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