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

Zeljka Korade,Thiago C Genaro-Mattos,Keri A Tallman,Wei Liu,Krassimira A Garbett,Katalin Koczok,Istvan Balogh,Karoly Mirnics,Ned A Porter

doi:10.1194/jlr.m079475

Zeljka Korade, Thiago C Genaro-Mattos + Show 7 more

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https://doi.org/10.1194/jlr.m079475

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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.

Highlights

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 cell with DHCR7 having reduced functional activity leads to elevated cellular levels of 7-DHC or 7-dehydrodesmosterol and, if a functioning DHCR24 is present in the cell, levels of 7-DHC can be used as the principal biomarker to identify a compromised DHCR7
The findings of our study can be summarized in several main points: 1) ARI and TRZ treatments significantly elevate 7-DHC levels and alter the 7-DHC/Chol ratio in human fibroblast (HF) regardless of genotype

Summary

Introduction

Smith-Lemli-Opitz syndrome is a recessive disorder caused by mutations in 7-dehydrocholesterol reductase (DHCR) 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). Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder caused by mutations of 7-dehydrocholesterol reductase (DHCR), the gene that encodes DHCR7, the. While there are many studies on SLOS patients to date, the health status of HET DHCR7+/ mutation carriers has been less extensively investigated. The Dhcr7+/ mutant mice show increased dominance and elevated head-twitch response to a challenge with a 5-HT2A agonist [18]

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