title: Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes.
abstract: Acetaminophen (APAP) is a readily available over-the-counter drug and is one of the most commonly used analgesics/antipyretics worldwide. Large interindividual variation in susceptibility toward APAP-induced liver failure has been reported. However, the exact underlying factors causing this variability in susceptibility are still largely unknown. The aim of this study was to better understand this variability in response to APAP by evaluating interindividual differences in gene expression changes and APAP metabolite formation in primary human hepatocytes (PHH) from several donors (n = 5) exposed in vitro to a non-toxic to toxic APAP dose range. To evaluate interindividual variation, gene expression data/levels of metabolites were plotted against APAP dose/donor. The correlation in APAP dose response between donors was calculated by comparing data points from one donor to the data points of all other donors using a Pearson-based correlation analysis. From that, a correlation score/donor for each gene/metabolite was defined, representing the similarity of the omics response to APAP in PHH of a particular donor to all other donors. The top 1 % highest variable genes were selected for further evaluation using gene set overrepresentation analysis. The biological processes in which the genes with high interindividual variation in expression were involved include liver regeneration, inflammatory responses, mitochondrial stress responses, hepatocarcinogenesis, cell cycle, and drug efficacy. Additionally, the interindividual variation in the expression of these genes could be associated with the variability in expression levels of hydroxyl/methoxy-APAP and C8H13O5N-APAP-glucuronide. The before-mentioned metabolites or their derivatives have also been reported in blood of humans exposed to therapeutic APAP doses. Possibly these findings can contribute to elucidating the causative factors of interindividual susceptibility toward APAP.
authors.affiliation: Department of Toxicogenomics, Maastricht University, Universiteitssingel 50, Room 4.112 UNS 50, 6229 ER, Maastricht, The Netherlands. marlon.jetten@maastrichtuniversity.nl.
authors.forename: Marlon J A
authors.initials: MJ
authors.lastname: Jetten
authors.affiliation: RIKILT, Institute of Food Safety, Wageningen UR, PO Box 230, 6700 AE, Wageningen, The Netherlands.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Ruiz-Aracama
authors.affiliation: Department of Toxicogenomics, Maastricht University, Universiteitssingel 50, Room 4.112 UNS 50, 6229 ER, Maastricht, The Netherlands.
authors.forename: Maarten L J
authors.initials: ML
authors.lastname: Coonen
authors.affiliation: Department of Toxicogenomics, Maastricht University, Universiteitssingel 50, Room 4.112 UNS 50, 6229 ER, Maastricht, The Netherlands.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Claessen
authors.affiliation: Department of Toxicogenomics, Maastricht University, Universiteitssingel 50, Room 4.112 UNS 50, 6229 ER, Maastricht, The Netherlands.
authors.forename: Marcel H M
authors.initials: MH
authors.lastname: van Herwijnen
authors.affiliation: RIKILT, Institute of Food Safety, Wageningen UR, PO Box 230, 6700 AE, Wageningen, The Netherlands.
authors.forename: Arjen
authors.initials: A
authors.lastname: Lommen
authors.affiliation: Department of Toxicogenomics, Maastricht University, Universiteitssingel 50, Room 4.112 UNS 50, 6229 ER, Maastricht, The Netherlands.
authors.forename: Joost H M
authors.initials: JH
authors.lastname: van Delft
authors.affiliation: RIKILT, Institute of Food Safety, Wageningen UR, PO Box 230, 6700 AE, Wageningen, The Netherlands.
authors.forename: Ad A C M
authors.initials: AA
authors.lastname: Peijnenburg
authors.affiliation: Department of Toxicogenomics, Maastricht University, Universiteitssingel 50, Room 4.112 UNS 50, 6229 ER, Maastricht, The Netherlands.
authors.forename: Jos C S
authors.initials: JC
authors.lastname: Kleinjans
mesh_terms: D000082:Acetaminophen / Q000378:metabolism* / Q000633:toxicity*; D065767:Activation, Metabolic; D018712:Analgesics, Non-Narcotic / Q000378:metabolism* / Q000633:toxicity*; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D055432:Metabolomics; D010641:Phenotype; D061251:Primary Cell Culture
chemical_list: D018712:Analgesics, Non-Narcotic; D005819:Genetic Markers; D000082:Acetaminophen
keywords: Aflatoxin b1; Benzo(a)pyrene; DNA methylation; Gene expression; Interindividual variation; Primary human hepatocytes