title: 'Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans.
abstract: Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure acetaminophen exposure after profound liver toxicity has already occurred. Furthermore, these tests do not provide mechanistic information. Here, 'omics techniques (global analysis of metabolomic/gene-expression responses) may provide additional insight. To better understand acetaminophen-induced responses at low doses, we evaluated the effects of (sub-)therapeutic acetaminophen doses on metabolite formation and global gene-expression changes (including, for the first time, full-genome human miRNA expression changes) in blood/urine samples from healthy human volunteers. Many known and several new acetaminophen-metabolites were detected, in particular in relation to hepatotoxicity-linked, oxidative metabolism of acetaminophen. Transcriptomic changes indicated immune-modulating effects (2g dose) and oxidative stress responses (4g dose). For the first time, effects of acetaminophen on full-genome human miRNA expression have been considered and confirmed the findings on mRNA level. 'Omics techniques outperformed clinical chemistry tests and revealed novel response pathways to acetaminophen in humans. Although no definitive conclusion about potential immunotoxic effects of acetaminophen can be drawn from this study, there are clear indications that the immune system is triggered even after intake of low doses of acetaminophen. Also, oxidative stress-related gene responses, similar to those seen after high dose acetaminophen exposure, suggest the occurrence of possible pre-toxic effects of therapeutic acetaminophen doses. Possibly, these effects are related to dose-dependent increases in levels of hepatotoxicity-related metabolites.
authors.affiliation: Department of Toxicogenomics, Maastricht University, Universitiessingel 50 6229 ER Maastricht, The Netherlands. j.vandelft@maastrichtuniversity.nl
authors.forename: Marlon J A
authors.initials: MJ
authors.lastname: Jetten
authors.forename: Stan
authors.initials: S
authors.lastname: Gaj
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Ruiz-Aracama
authors.forename: Theo M
authors.initials: TM
authors.lastname: de Kok
authors.forename: Joost H M
authors.initials: JH
authors.lastname: van Delft
authors.forename: Arjen
authors.initials: A
authors.lastname: Lommen
authors.forename: Eugene P
authors.initials: EP
authors.lastname: van Someren
authors.forename: Danyel G J
authors.initials: DG
authors.lastname: Jennen
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Claessen
authors.forename: Ad A C M
authors.initials: AA
authors.lastname: Peijnenburg
authors.forename: Rob H
authors.initials: RH
authors.lastname: Stierum
authors.forename: Jos C S
authors.initials: JC
authors.lastname: Kleinjans
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D015894:Genome, Human; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D059467:Transcriptome
chemical_list: D018712:Analgesics, Non-Narcotic; D035683:MicroRNAs; D012333:RNA, Messenger; D000082:Acetaminophen