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001-es BibID:BIBFORM072690
Első szerző:Korade, Zeljka
Cím: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
Dátum:2017
ISSN:0022-2275
Megjegyzések: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.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
7-dehydrocholesterol
aripiprazole
trazodone
fibroblasts
carriers
antipsychotics
Megjelenés:Journal Of Lipid Research 58 : 11 (2017), p. 2139-2146. -
További szerzők:Genaro-Mattos, Thiago C. Tallman, Keri A. Liu, Wei Garbett, Krassimira A. Koczok Katalin (1979-) (labororvos) Balogh István (1972-) (molekuláris biológus, genetikus) Mirnics Károly Porter, Ned A.
Pályázati támogatás:GINOP-2.3.2-15-2016-00039
GINOP
Internet cím:DOI
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001-es BibID:BIBFORM068909
Első szerző:Korade, Zeljka
Cím:The Effect of Small Molecules on Sterol Homeostasis: Measuring 7-Dehydrocholesterol in Dhcr7-Deficient Neuro2a Cells and Human Fibroblasts / Korade Zeljka, Kim Hye-Young H., Tallman Keri A., Liu Wei, Koczok Katalin, Balogh Istvan, Xu Libin, Mirnics Karoly, Porter Ned A.
Dátum:2016
ISSN:0022-2623 1520-4804
Megjegyzések:Well-established cell culture models were combined with new analytical methods to assess the effects of small molecules on the cholesterol biosynthesis pathway. The analytical protocol, which is based on sterol derivation with the dienolphile PTAD, was found to be reliable for the analysis of 7-DHC and desmosterol. The PTAD method was applied to the screening of a small library of pharmacologically active substances, and the effect of compounds on the cholesterol pathway was determined. Of some 727 compounds, over 30 compounds decreased 7-DHC in Dhcr7-deficient Neuro2a cells. The examination of chemical structures of active molecules in the screen grouped the compounds into distinct categories. In addition to statins, our screen found that SERMs, antifungals, and several antipsychotic medications reduced levels of 7-DHC. The activities of selected compounds were verified in human fibroblasts derived from Smith?Lemli?Opitz syndrome (SLOS) patients and linked to specific transformations in the cholesterol biosynthesis pathway.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Journal Of Medicinal Chemistry 59 : 3 (2016), p. 1102-1115. -
További szerzők:Kim, Hye-Young H. Tallman, Keri A. Liu, Wei Koczok Katalin (1979-) (labororvos) Balogh István (1972-) (molekuláris biológus, genetikus) Xu, Libin Mirnics Károly Porter, Ned A.
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DOI
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