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  Proteomics Analysis of Monocyte-Derived Hepatocyte-Like Cells Identifies Integrin Beta 3 as a Specific Biomarker for Drug-Induced Liver Injury by Diclofenac

Dragoi, D., Benesic, A., Pichler, G., Kulak, N. A., Bartsch, H. S., & Gerbes, A. L. (2018). Proteomics Analysis of Monocyte-Derived Hepatocyte-Like Cells Identifies Integrin Beta 3 as a Specific Biomarker for Drug-Induced Liver Injury by Diclofenac. Frontiers in Pharmacology, 9: 699. doi:10.3389/fphar.2018.00699.

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 Creators:
Dragoi, Diana1, Author
Benesic, Andreas1, Author
Pichler, Garwin2, Author              
Kulak, Nils A.2, Author              
Bartsch, Harald S.1, Author
Gerbes, Alexander L.1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: IN-VITRO; WIDE; QUANTIFICATION; DIAGNOSISPharmacology & Pharmacy; DILI; biomarker; proteomics; drug-development; monocyte-derived hepatocyte-like cells;
 Abstract: Idiosyncratic drug-induced liver injury (iDILI) is a major cause of acute liver failure resulting in liver transplantation or death. Prediction and diagnosis of iDILI remain a great challenge, as current models provide unsatisfying results in terms of sensitivity, specificity, and prognostic value. The absence of appropriate tools for iDILI detection also impairs the development of reliable biomarkers. Here, we report on a new method for identification of drug-specific biomarkers. We combined the advantages of monocyte-derived hepatocyte-like (MH) cells, able to mimic individual characteristics, with those of a novel mass spectrometry-based proteomics technology to assess potential biomarkers for Diclofenac-induced DILI. We found over 2,700 proteins differentially regulated in MH cells derived from individual patients. Herefrom, we identified integrin beta 3 (ITGB3) to be specifically upregulated in Diclofenac-treated MH cells from Diclofenac-DILI patients compared to control groups. Finally, we validated ITGB3 by flow cytometry analysis of whole blood and histological staining of liver biopsies derived from patients diagnosed with Diclofenac-DILI. In summary, our results show that biomarker candidates can be identified by proteomics analysis of MH cells. Application of this method to a broader range of drugs in the future will exploit its full potential for the development of drug-specific biomarkers. Data are available via ProteomeXchange with identifier PXD008918.

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Language(s): eng - English
 Dates: 2018
 Publication Status: Published online
 Pages: 10
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000437296100001
DOI: 10.3389/fphar.2018.00699
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Title: Frontiers in Pharmacology
Source Genre: Journal
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Publ. Info: AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND : FRONTIERS MEDIA SA
Pages: - Volume / Issue: 9 Sequence Number: 699 Start / End Page: - Identifier: ISSN: 1663-9812