title: Proteomic profiling in incubation medium of mouse, rat and human precision-cut liver slices for biomarker detection regarding acute drug-induced liver injury.
abstract: Drug-induced liver injury is one of the leading causes of drug withdrawal from the market. In this study, we investigated the applicability of protein profiling of the incubation medium of human, mouse and rat precision-cut liver slices (PCLS) exposed to liver injury-inducing drugs for biomarker identification, using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. PCLS were incubated with acetaminophen (APAP), 3-acetamidophenol, diclofenac and lipopolysaccharide for 24-48 h. PCLS medium from all species treated with APAP demonstrated similar changes in protein profiles, as previously found in mouse urine after APAP-induced liver injury, including the same key proteins: superoxide dismutase 1, carbonic anhydrase 3 and calmodulin. Further analysis showed that the concentration of hepcidin, a hepatic iron-regulating hormone peptide, was reduced in PCLS medium after APAP treatment, resembling the decreased mouse plasma concentrations of hepcidin observed after APAP treatment. Interestingly, comparable results were obtained after 3-acetamidophenol incubation in rat and human, but not mouse PCLS. Incubation with diclofenac, but not with lipopolysaccharide, resulted in the same toxicity parameters as observed for APAP, albeit to a lesser extent. In conclusion, proteomics can be applied to identify potential translational biomarkers using the PCLS system.
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, the Netherlands.
authors.forename: Rachel P L
authors.initials: RP
authors.lastname: van Swelm
authors.forename: Mackenzie
authors.initials: M
authors.lastname: Hadi
authors.forename: Coby M M
authors.initials: CM
authors.lastname: Laarakkers
authors.forename: Rosalinde
authors.initials: R
authors.lastname: Masereeuw
authors.forename: Geny M M
authors.initials: GM
authors.lastname: Groothuis
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D015415:Biomarkers / Q000652:urine*; D002147:Calmodulin / Q000378:metabolism; D024403:Carbonic Anhydrase III / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis*; D004008:Diclofenac / Q000008:administration & dosage / Q000633:toxicity; D020869:Gene Expression Profiling; D064451:Hepcidins / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D040901:Proteomics; D051381:Rats; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D018675:Toxicity Tests
chemical_list: D015415:Biomarkers; D002147:Calmodulin; D064451:Hepcidins; D008070:Lipopolysaccharides; C000606290:SOD1 protein, human; D004008:Diclofenac; D000082:Acetaminophen; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D024403:Carbonic Anhydrase III
keywords: Precision-cut liver slices; acetaminophen; diclofenac; drug-induced liver injury; hepcidin; proteomics profiling