Identification and characterization of prescription drugs that change levels of 7-dehydrocholesterol and desmosterol

Phillip A. Wages, Hye Young H. Kim, Zeljka Korade, Ned A. Porter

Research output: Contribution to journalArticle

Abstract

Regulating blood cholesterol (Chol) levels by pharmacotherapy has successfully improved cardiovascular health. There is growing interest in the role of Chol precursors in the treatment of diseases. One sterol precursor, desmosterol (Des), is a potential pharmacological target for inflammatory and neurodegenerative disorders. However, elevating levels of the precursor 7-dehydrocholesterol (7-DHC) by inhibiting the enzyme 7-dehydrocholesterol reductase is linked to teratogenic outcomes. Thus, altering the sterol profile may either increase risk toward an adverse outcome or confer therapeutic benefit depending on the metabolite affected by the pharmacophore. In order to characterize any unknown activity of drugs on Chol biosynthesis, a chemical library of Food and Drug Administration-approved drugs was screened for the potential to modulate 7-DHC or Des levels in a neural cell line. Over 20% of the collection was shown to impact Chol biosynthesis, including 75 compounds that alter 7-DHC levels and 49 that modulate Des levels. Evidence is provided that three tyrosine kinase inhibitors, imatinib, ponatinib, and masitinib, elevate Des levels as well as other substrates of 24-dehydrocholesterol reductase, the enzyme responsible for converting Des to Chol. Additionally, the mechanism of action for ponatinib and masitinib was explored, demonstrating that protein levels are decreased as a result of treatment with these drugs.

Original languageEnglish (US)
Pages (from-to)1916-1926
Number of pages11
JournalJournal of Lipid Research
Volume59
Issue number10
DOIs
StatePublished - Jan 1 2018

Fingerprint

Desmosterol
Prescription Drugs
Cholesterol
Biosynthesis
Sterols
Pharmaceutical Preparations
Small Molecule Libraries
Drug therapy
Enzymes
United States Food and Drug Administration
Metabolites
Neurodegenerative Diseases
Protein-Tyrosine Kinases
7-dehydrocholesterol
Oxidoreductases
Blood
Therapeutics
Cells
Health
Pharmacology

Keywords

  • 24-dehydrocholesterol reductase
  • 7-dehydrocholesterol reductase
  • Cholesterol/biosynthesis
  • Drug therapy
  • High-throughput screening
  • Mass spectrometry
  • Sterols

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Identification and characterization of prescription drugs that change levels of 7-dehydrocholesterol and desmosterol. / Wages, Phillip A.; Kim, Hye Young H.; Korade, Zeljka; Porter, Ned A.

In: Journal of Lipid Research, Vol. 59, No. 10, 01.01.2018, p. 1916-1926.

Research output: Contribution to journalArticle

@article{1beed19a6c5442169ee23ee8bcad7683,
title = "Identification and characterization of prescription drugs that change levels of 7-dehydrocholesterol and desmosterol",
abstract = "Regulating blood cholesterol (Chol) levels by pharmacotherapy has successfully improved cardiovascular health. There is growing interest in the role of Chol precursors in the treatment of diseases. One sterol precursor, desmosterol (Des), is a potential pharmacological target for inflammatory and neurodegenerative disorders. However, elevating levels of the precursor 7-dehydrocholesterol (7-DHC) by inhibiting the enzyme 7-dehydrocholesterol reductase is linked to teratogenic outcomes. Thus, altering the sterol profile may either increase risk toward an adverse outcome or confer therapeutic benefit depending on the metabolite affected by the pharmacophore. In order to characterize any unknown activity of drugs on Chol biosynthesis, a chemical library of Food and Drug Administration-approved drugs was screened for the potential to modulate 7-DHC or Des levels in a neural cell line. Over 20{\%} of the collection was shown to impact Chol biosynthesis, including 75 compounds that alter 7-DHC levels and 49 that modulate Des levels. Evidence is provided that three tyrosine kinase inhibitors, imatinib, ponatinib, and masitinib, elevate Des levels as well as other substrates of 24-dehydrocholesterol reductase, the enzyme responsible for converting Des to Chol. Additionally, the mechanism of action for ponatinib and masitinib was explored, demonstrating that protein levels are decreased as a result of treatment with these drugs.",
keywords = "24-dehydrocholesterol reductase, 7-dehydrocholesterol reductase, Cholesterol/biosynthesis, Drug therapy, High-throughput screening, Mass spectrometry, Sterols",
author = "Wages, {Phillip A.} and Kim, {Hye Young H.} and Zeljka Korade and Porter, {Ned A.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1194/jlr.M086991",
language = "English (US)",
volume = "59",
pages = "1916--1926",
journal = "Journal of Lipid Research",
issn = "0022-2275",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "10",

}

TY - JOUR

T1 - Identification and characterization of prescription drugs that change levels of 7-dehydrocholesterol and desmosterol

AU - Wages, Phillip A.

AU - Kim, Hye Young H.

AU - Korade, Zeljka

AU - Porter, Ned A.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Regulating blood cholesterol (Chol) levels by pharmacotherapy has successfully improved cardiovascular health. There is growing interest in the role of Chol precursors in the treatment of diseases. One sterol precursor, desmosterol (Des), is a potential pharmacological target for inflammatory and neurodegenerative disorders. However, elevating levels of the precursor 7-dehydrocholesterol (7-DHC) by inhibiting the enzyme 7-dehydrocholesterol reductase is linked to teratogenic outcomes. Thus, altering the sterol profile may either increase risk toward an adverse outcome or confer therapeutic benefit depending on the metabolite affected by the pharmacophore. In order to characterize any unknown activity of drugs on Chol biosynthesis, a chemical library of Food and Drug Administration-approved drugs was screened for the potential to modulate 7-DHC or Des levels in a neural cell line. Over 20% of the collection was shown to impact Chol biosynthesis, including 75 compounds that alter 7-DHC levels and 49 that modulate Des levels. Evidence is provided that three tyrosine kinase inhibitors, imatinib, ponatinib, and masitinib, elevate Des levels as well as other substrates of 24-dehydrocholesterol reductase, the enzyme responsible for converting Des to Chol. Additionally, the mechanism of action for ponatinib and masitinib was explored, demonstrating that protein levels are decreased as a result of treatment with these drugs.

AB - Regulating blood cholesterol (Chol) levels by pharmacotherapy has successfully improved cardiovascular health. There is growing interest in the role of Chol precursors in the treatment of diseases. One sterol precursor, desmosterol (Des), is a potential pharmacological target for inflammatory and neurodegenerative disorders. However, elevating levels of the precursor 7-dehydrocholesterol (7-DHC) by inhibiting the enzyme 7-dehydrocholesterol reductase is linked to teratogenic outcomes. Thus, altering the sterol profile may either increase risk toward an adverse outcome or confer therapeutic benefit depending on the metabolite affected by the pharmacophore. In order to characterize any unknown activity of drugs on Chol biosynthesis, a chemical library of Food and Drug Administration-approved drugs was screened for the potential to modulate 7-DHC or Des levels in a neural cell line. Over 20% of the collection was shown to impact Chol biosynthesis, including 75 compounds that alter 7-DHC levels and 49 that modulate Des levels. Evidence is provided that three tyrosine kinase inhibitors, imatinib, ponatinib, and masitinib, elevate Des levels as well as other substrates of 24-dehydrocholesterol reductase, the enzyme responsible for converting Des to Chol. Additionally, the mechanism of action for ponatinib and masitinib was explored, demonstrating that protein levels are decreased as a result of treatment with these drugs.

KW - 24-dehydrocholesterol reductase

KW - 7-dehydrocholesterol reductase

KW - Cholesterol/biosynthesis

KW - Drug therapy

KW - High-throughput screening

KW - Mass spectrometry

KW - Sterols

UR - http://www.scopus.com/inward/record.url?scp=85054084098&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054084098&partnerID=8YFLogxK

U2 - 10.1194/jlr.M086991

DO - 10.1194/jlr.M086991

M3 - Article

C2 - 30087204

AN - SCOPUS:85054084098

VL - 59

SP - 1916

EP - 1926

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

IS - 10

ER -