title: Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen.
abstract: The diagnosis of drug-induced liver injury is hindered by the limited utility of clinical chemistries. We have shown that hepatotoxicants can produce peripheral blood transcriptome "signatures" (PBTS) in rodents and humans. In this study, 42 adults were treated with acetaminophen (APAP; 1 g every 6 hours) for seven days, followed by three days of placebo. Eleven subjects received only placebo. After five days, 12 subjects (30%) had increases in serum alanine aminotransferase (ALT) levels ("responders"). PBTS of 707 and 760 genes, respectively, could distinguish responders and nonresponders from placebos. Functional analysis of the responder PBTS revealed increased expression of genes involved in TH2-mediated and innate immune responses, whereas the nonresponders demonstrated increased gene expression consistent with a tolerogenic immune response. Taken together, these observations suggest that the clinical subjects with transient increases in serum ALT failed to maintain or intensify a hepatic tolerogenic immune response.
authors.affiliation: National Institute of Environmental Health Sciences, Molecular Genomics Core, National Institute of Health, Research Triangle Park, North Carolina, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Fannin
authors.affiliation: National Institute of Environmental Health Sciences, Molecular Genomics Core, National Institute of Health, Research Triangle Park, North Carolina, USA.
authors.forename: K
authors.initials: K
authors.lastname: Gerrish
authors.affiliation: National Institute of Environmental Health Sciences, Molecular Genomics Core, National Institute of Health, Research Triangle Park, North Carolina, USA.
authors.forename: S O
authors.initials: SO
authors.lastname: Sieber
authors.affiliation: National Institute of Environmental Health Sciences, Biostatistics and Computational Biology Branch, National Institute of Health, Research Triangle Park, North Carolina, USA.
authors.forename: P R
authors.initials: PR
authors.lastname: Bushel
authors.affiliation: Hamner - University of North Carolina Institute for Drug Safety Sciences, Research Triangle Park, North Carolina, USA.
authors.forename: P B
authors.initials: PB
authors.lastname: Watkins
authors.affiliation: National Institute of Environmental Health Sciences, National Toxicology Program, Biomolecular Screening Branch, National Institute of Health, Research Triangle Park, North Carolina, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Paules
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects*; D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods*; D020869:Gene Expression Profiling; D005819:Genetic Markers; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D011237:Predictive Value of Tests; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000097:blood*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D059467:Transcriptome / Q000187:drug effects*; D015854:Up-Regulation
chemical_list: D018712:Analgesics, Non-Narcotic; D005819:Genetic Markers; D012333:RNA, Messenger; D000082:Acetaminophen; D000410:Alanine Transaminase