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Bioinformatics and mass spectrometry-based proteomics reveal alcohol dehydrogenase 1B as a blood biomarker candidate to monitor acetaminophen-induced liver injury

ABSTRACT: Acute liver injury (ALI) is a severe disorder resulting from excessive hepatocyte cell death and frequently caused by acetaminophen intoxication. Clinical management of ALI progression is hampered by the dearth of blood biomarkers available. In this study, a bioinformatics workflow was developed to screen Omics databases and identify potential biomarkers for hepatocyte cell death. Then, discovery proteomics was harnessed to select among these candidates those that were specifically detected into the blood of acetaminophen-induced ALI patients. Among these candidates, the isoenzyme alcohol dehydrogenase 1B (ADH1B) was massively leaked into the blood. To evaluate ADH1B, we developed a targeted proteomics assay and quantified ADH1B in serum samples collected at different times from 17 patients admitted for acetaminophen-induced ALI. Serum ADH1B concentrations increased markedly during the acute phase of the disease and dropped to undetectable levels during recovery. In contrast to alanine aminotransferase activity, the rapid drop in circulating ADH1B concentrations was followed by an improvement of the in-ternational normalized ratio (INR) within 10 to 48h and was associated with a favorable outcome. In conclusion, the combination of Omics data exploration and proteomics revealed ADH1B as a new blood biomarker which could be useful to improve the monitoring of acetaminophen-induced ALI.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Serum

DISEASE(S): Liver Disease

SUBMITTER: Hesse Anne-Marie

LAB HEAD: Virginie Brun

PROVIDER: PXD028082 | Pride | 2021-11-29

REPOSITORIES: Pride

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Project description:Sluka2016 - Acetaminophen metabolism Liver metabolism of Acetaminophen: Acetaminophen (APAP) is metabolized in the liver in both Phase I and Phase II reactions. Phase II reactions convert APAP to APAP-glucuronide and APAP-sulfate. Phase I reactions involve Cytochrome P450 mediated (mostly Cyp450-2E1 and -1A2) conversion of APAP to N-acetyle-p-quinoneimine (NAPQI), which goes on to react with cellular nucleophiles such as glutathione (GSH). At high doses of APAP significant GSH depletion in hepatocyte occurs resulting in cell necrosis and and in extreme cases death. This model is described in the article: A Liver-Centric Multiscale Modeling Framework for Xenobiotics. Sluka JP, Fu X, Swat M, Belmonte JM, Cosmanescu A, Clendenon SG, Wambaugh JF, Glazier JA. PLoS ONE 2016; 11(9): e0162428 Abstract: We describe a multi-scale, liver-centric in silico modeling framework for acetaminophen pharmacology and metabolism. We focus on a computational model to characterize whole body uptake and clearance, liver transport and phase I and phase II metabolism. We do this by incorporating sub-models that span three scales; Physiologically Based Pharmacokinetic (PBPK) modeling of acetaminophen uptake and distribution at the whole body level, cell and blood flow modeling at the tissue/organ level and metabolism at the sub-cellular level. We have used standard modeling modalities at each of the three scales. In particular, we have used the Systems Biology Markup Language (SBML) to create both the whole-body and sub-cellular scales. Our modeling approach allows us to run the individual sub-models separately and allows us to easily exchange models at a particular scale without the need to extensively rework the sub-models at other scales. In addition, the use of SBML greatly facilitates the inclusion of biological annotations directly in the model code. The model was calibrated using human in vivo data for acetaminophen and its sulfate and glucuronate metabolites. We then carried out extensive parameter sensitivity studies including the pairwise interaction of parameters. We also simulated population variation of exposure and sensitivity to acetaminophen. Our modeling framework can be extended to the prediction of liver toxicity following acetaminophen overdose, or used as a general purpose pharmacokinetic model for xenobiotics. This model is hosted on BioModels Database and identified by: BIOMD0000000624. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

			Action	DRS
	20210615_ALI.mzid.gz	Mzid
	HF2_005037.mgf	Mgf
	HF2_005037.raw	Raw
	HF2_005041.mgf	Mgf
	HF2_005041.raw	Raw

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Bioinformatics and mass spectrometry-based proteomics reveal alcohol dehydrogenase 1B as a blood biomarker candidate to monitor acetaminophen-induced liver injury

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