Tandem mass tag-based quantitative proteomic profiling identifies candidate serum biomarkers of drug-induced liver injury in humans.
Creators: name: Ravindra, Kodihalli C
name: Vaidya, Vishal S
name: Wang, Zhenyu
name: Federspiel, Joel D
name: Virgen-Slane, Richard
name: Everley, Robert A
name: Grove, Jane I
name: Stephens, Camilla
name: Ocana, Mireia F
name: Robles-Díaz, Mercedes
name: Isabel Lucena, M
name: Andrade, Raul J
name: Atallah, Edmond
name: Gerbes, Alexander L
name: Weber, Sabine
name: Cortez-Pinto, Helena
name: Fowell, Andrew J
name: Hussaini, Hyder
name: Bjornsson, Einar S
name: Patel, Janisha
name: Stirnimann, Guido
name: Verma, Sumita
name: Elsharkawy, Ahmed M
name: Griffiths, William JH
name: Hyde, Craig
name: Dear, James W
name: Aithal, Guruprasad P
name: Ramaiah, Shashi K
Publisher: name: Apollo - University of Cambridge Repository
Year: 2023
Subjects: Humans
Proteomics
Chemical and Drug Induced Liver Injury
Argininosuccinate Synthase
Biomarkers
CD8 Antigens
Fructose

description: Acknowledgements: We thank all our study participants and research study teams for their involvement in providing resources for this research. This article is supported by the members of COST Action “CA17112 - Prospective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology), www.cost.eu including J.I.G., C.S., M.R.-D., M.I.L., R.J.A., E.A., A.L.G., S.W., H.C.-P., E.S.B., G.S. and G.P.A. We acknowledge support from the members of the PRO-EURO-DILI Network for input on aligning protocols across multiple centers as well as in the case adjudication. We acknowledge Melanie Lingaya, Ryan Criswell, Deborah Hart, James Stejskal, Richard Giovanelli, Kelly Fader, and Heather Llewellyn for their assistance with sample processing. Funding was made available from the Drug Safety Research and Development department within Pfizer’s Worldwide Research Development and Medical. J.I.G., E.A., and G.P.A. are supported by NIHR Nottingham Biomedical Research Centre [BRC-1215-20003]. The views expressed are those of the authors and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health.
description: Funder: Funding was made available from the Drug Safety Research and Development department within Pfizer’s Worldwide Research Development and Medical. JIG, EA and GPA are supported by NIHR Nottingham Biomedical Research Centre [BRC-1215-6 20003].
description: Diagnosis of drug-induced liver injury (DILI) and its distinction from other liver diseases are significant challenges in drug development and clinical practice. Here, we identify, confirm, and replicate the biomarker performance characteristics of candidate proteins in patients with DILI at onset (DO; n = 133) and follow-up (n = 120), acute non-DILI at onset (NDO; n = 63) and follow-up (n = 42), and healthy volunteers (HV; n = 104). Area under the receiver operating characteristic curve (AUC) for cytoplasmic aconitate hydratase, argininosuccinate synthase, carbamoylphosphate synthase, fumarylacetoacetase, fructose-1,6-bisphosphatase 1 (FBP1) across cohorts achieved near complete separation (range: 0.94-0.99) of DO and HV. In addition, we show that FBP1, alone or in combination with glutathione S-transferase A1 and leukocyte cell-derived chemotaxin 2, could potentially assist in clinical diagnosis by distinguishing NDO from DO (AUC range: 0.65-0.78), but further technical and clinical validation of these candidate biomarkers is needed.