The effects of rosuvastatin and the CYP51A1 inhibitor LEK-935 on the proteome of primary human hepatocytes

Martin Wörner, Katja Melchior, K. Monostory, Jean Marc Pascussi, Christian G. Huber, Rita Bernhardt

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Elevated amounts of cholesterol are thought to be involved in several severe diseases. Despite the fact that many studies have been performed and published, the action of cholesterol-lowering agents used to diminish the plasma cholesterol level is not fully understood yet. In this study, the effects of the HMG-CoA reductase inhibitor rosuvastatin and the new CYP51A1 inhibitor 2-((3,4-dichlorophenethyl)(propyl)amino)-1-(pyridin-3- yl)ethanol (LEK-935) on the proteome of primary human hepatocytes were analyzed for the first time. To get an idea about interindividual differences, two different human donors were used. The cytosolic and microsomal fractions of the cells were analyzed in a semiquantitative manner by two-dimensional-polyacrylamide gel electrophoresis and capillary high-performance liquid chromatography-mass spectrometry, respectively. Thereby, a set of 44 proteins was found to be differentially presented. The chosen experimental set-up was validated by proteins already known to be affected by statins and involved in the cholesterol biosynthesis. Other proteins found to be regulated cannot be directly related to cholesterol metabolism and have not been described to be affected by cholesterol-lowering agents so far. Some of these proteins may represent interesting targets for further investigations into the analysis of severe side-effects as well as pleiotropic effects of the statins. During the proteome analysis of the two different donors, interindividual differences were observed that were validated by realtime reverse transcription-polymerase chain reaction measurements. Thus, new information and a deeper insight into the processes taking place inside cells treated with cholesterol-lowering agents can be drawn from this study.

Original languageEnglish
Pages (from-to)414-418
Number of pages5
JournalDrug Metabolism and Disposition
Volume40
Issue number3
DOIs
Publication statusPublished - Mar 2012

Fingerprint

Proteome
Hepatocytes
Cholesterol
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Proteins
Electrophoresis, Gel, Two-Dimensional
Hypercholesterolemia
Reverse Transcription
Rosuvastatin Calcium
Mass Spectrometry
Ethanol
High Pressure Liquid Chromatography
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

The effects of rosuvastatin and the CYP51A1 inhibitor LEK-935 on the proteome of primary human hepatocytes. / Wörner, Martin; Melchior, Katja; Monostory, K.; Pascussi, Jean Marc; Huber, Christian G.; Bernhardt, Rita.

In: Drug Metabolism and Disposition, Vol. 40, No. 3, 03.2012, p. 414-418.

Research output: Contribution to journalArticle

Wörner, Martin ; Melchior, Katja ; Monostory, K. ; Pascussi, Jean Marc ; Huber, Christian G. ; Bernhardt, Rita. / The effects of rosuvastatin and the CYP51A1 inhibitor LEK-935 on the proteome of primary human hepatocytes. In: Drug Metabolism and Disposition. 2012 ; Vol. 40, No. 3. pp. 414-418.
@article{3c87d17c9a8f4e6085ca6c426b6eea9d,
title = "The effects of rosuvastatin and the CYP51A1 inhibitor LEK-935 on the proteome of primary human hepatocytes",
abstract = "Elevated amounts of cholesterol are thought to be involved in several severe diseases. Despite the fact that many studies have been performed and published, the action of cholesterol-lowering agents used to diminish the plasma cholesterol level is not fully understood yet. In this study, the effects of the HMG-CoA reductase inhibitor rosuvastatin and the new CYP51A1 inhibitor 2-((3,4-dichlorophenethyl)(propyl)amino)-1-(pyridin-3- yl)ethanol (LEK-935) on the proteome of primary human hepatocytes were analyzed for the first time. To get an idea about interindividual differences, two different human donors were used. The cytosolic and microsomal fractions of the cells were analyzed in a semiquantitative manner by two-dimensional-polyacrylamide gel electrophoresis and capillary high-performance liquid chromatography-mass spectrometry, respectively. Thereby, a set of 44 proteins was found to be differentially presented. The chosen experimental set-up was validated by proteins already known to be affected by statins and involved in the cholesterol biosynthesis. Other proteins found to be regulated cannot be directly related to cholesterol metabolism and have not been described to be affected by cholesterol-lowering agents so far. Some of these proteins may represent interesting targets for further investigations into the analysis of severe side-effects as well as pleiotropic effects of the statins. During the proteome analysis of the two different donors, interindividual differences were observed that were validated by realtime reverse transcription-polymerase chain reaction measurements. Thus, new information and a deeper insight into the processes taking place inside cells treated with cholesterol-lowering agents can be drawn from this study.",
author = "Martin W{\"o}rner and Katja Melchior and K. Monostory and Pascussi, {Jean Marc} and Huber, {Christian G.} and Rita Bernhardt",
year = "2012",
month = "3",
doi = "10.1124/dmd.111.040402",
language = "English",
volume = "40",
pages = "414--418",
journal = "Drug Metabolism and Disposition",
issn = "0090-9556",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - The effects of rosuvastatin and the CYP51A1 inhibitor LEK-935 on the proteome of primary human hepatocytes

AU - Wörner, Martin

AU - Melchior, Katja

AU - Monostory, K.

AU - Pascussi, Jean Marc

AU - Huber, Christian G.

AU - Bernhardt, Rita

PY - 2012/3

Y1 - 2012/3

N2 - Elevated amounts of cholesterol are thought to be involved in several severe diseases. Despite the fact that many studies have been performed and published, the action of cholesterol-lowering agents used to diminish the plasma cholesterol level is not fully understood yet. In this study, the effects of the HMG-CoA reductase inhibitor rosuvastatin and the new CYP51A1 inhibitor 2-((3,4-dichlorophenethyl)(propyl)amino)-1-(pyridin-3- yl)ethanol (LEK-935) on the proteome of primary human hepatocytes were analyzed for the first time. To get an idea about interindividual differences, two different human donors were used. The cytosolic and microsomal fractions of the cells were analyzed in a semiquantitative manner by two-dimensional-polyacrylamide gel electrophoresis and capillary high-performance liquid chromatography-mass spectrometry, respectively. Thereby, a set of 44 proteins was found to be differentially presented. The chosen experimental set-up was validated by proteins already known to be affected by statins and involved in the cholesterol biosynthesis. Other proteins found to be regulated cannot be directly related to cholesterol metabolism and have not been described to be affected by cholesterol-lowering agents so far. Some of these proteins may represent interesting targets for further investigations into the analysis of severe side-effects as well as pleiotropic effects of the statins. During the proteome analysis of the two different donors, interindividual differences were observed that were validated by realtime reverse transcription-polymerase chain reaction measurements. Thus, new information and a deeper insight into the processes taking place inside cells treated with cholesterol-lowering agents can be drawn from this study.

AB - Elevated amounts of cholesterol are thought to be involved in several severe diseases. Despite the fact that many studies have been performed and published, the action of cholesterol-lowering agents used to diminish the plasma cholesterol level is not fully understood yet. In this study, the effects of the HMG-CoA reductase inhibitor rosuvastatin and the new CYP51A1 inhibitor 2-((3,4-dichlorophenethyl)(propyl)amino)-1-(pyridin-3- yl)ethanol (LEK-935) on the proteome of primary human hepatocytes were analyzed for the first time. To get an idea about interindividual differences, two different human donors were used. The cytosolic and microsomal fractions of the cells were analyzed in a semiquantitative manner by two-dimensional-polyacrylamide gel electrophoresis and capillary high-performance liquid chromatography-mass spectrometry, respectively. Thereby, a set of 44 proteins was found to be differentially presented. The chosen experimental set-up was validated by proteins already known to be affected by statins and involved in the cholesterol biosynthesis. Other proteins found to be regulated cannot be directly related to cholesterol metabolism and have not been described to be affected by cholesterol-lowering agents so far. Some of these proteins may represent interesting targets for further investigations into the analysis of severe side-effects as well as pleiotropic effects of the statins. During the proteome analysis of the two different donors, interindividual differences were observed that were validated by realtime reverse transcription-polymerase chain reaction measurements. Thus, new information and a deeper insight into the processes taking place inside cells treated with cholesterol-lowering agents can be drawn from this study.

UR - http://www.scopus.com/inward/record.url?scp=84857403501&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84857403501&partnerID=8YFLogxK

U2 - 10.1124/dmd.111.040402

DO - 10.1124/dmd.111.040402

M3 - Article

VL - 40

SP - 414

EP - 418

JO - Drug Metabolism and Disposition

JF - Drug Metabolism and Disposition

SN - 0090-9556

IS - 3

ER -