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

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.

• Authors: Zeljka Korade, Thiago C Genaro-Mattos, Keri A Tallman, Wei Liu, Krassimira A Garbett, Katalin Koczok, Istvan Balogh, Karoly Mirnics, Ned A Porter
• Journal: Journal of lipid research (J Lipid Res) Vol. 58 Issue 11 Pg. 2139-2146 (11 2017) ISSN: 1539-7262 [Electronic] United States
• PMID: 28972118 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Enzyme Inhibitors
• Aripiprazole
• Cholesterol
• Oxidoreductases Acting on CH-CH Group Donors
• 7-dehydrocholesterol reductase
• Trazodone

Topics

• Adult
• Aripiprazole (pharmacology)
• Cholesterol (biosynthesis)
• Enzyme Inhibitors (pharmacology)
• Female
• Fibroblasts (drug effects, metabolism)
• Humans
• Male
• Middle Aged
• Mutation
• Oxidoreductases Acting on CH-CH Group Donors (antagonists & inhibitors, genetics)
• Smith-Lemli-Opitz Syndrome (enzymology, genetics)
• Trazodone (pharmacology)