Format

Send to

Choose Destination
Liver Int. 2017 Jan;37(1):132-140. doi: 10.1111/liv.13174. Epub 2016 Jun 22.

Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury.

Author information

1
Affinity proteomics, SciLifeLab, School of Biotechnology, KTH-Royal Institute of Technology, Stockholm, Sweden.
2
Global Safety Assessment, Molecular Toxicology, Former AstraZeneca R&D, Södertälje, Sweden.
3
Department of Pharmacology, Addis Ababa University, Addis Ababa, Ethiopia.
4
Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden.
5
Department of Internal Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
6
Momenta Pharmaceuticals, Cambridge, MA, USA.
7
Department of Immunology, Genetics and Pathology, SciLifeLab, Uppsala University, Uppsala, Sweden.
8
Biochemistry Department, Natural and Medical Sciences Institute at the University of Tuebingen, Reutlingen, Germany.
9
Hepatology Department, Hôpital Pitié-Salpêtrière, Paris, France.
10
UGC Gastroenterologia y Hepatologia y Serv Farmacología Clínica, IBIMA, Hospital U Virgen de la Victoria, University of Malaga, Málaga, Spain.
11
The Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
12
Schools of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
13
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
14
AstraZeneca R&D, Innovative Medicines Personalised Healthcare & Biomarkers, SciLifeLab, Stockholm, Sweden.

Abstract

BACKGROUND & AIMS:

The occurrence of drug-induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls.

METHODS:

An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins.

RESULTS:

We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid-binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated.

CONCLUSIONS:

These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers.

KEYWORDS:

affinity proteomics; biomarker discovery; drug-induced liver injury; plasma profiling; suspension bead arrays

PMID:
27224670
PMCID:
PMC5215406
DOI:
10.1111/liv.13174
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center