title: Acetaminophen dosing of humans results in blood transcriptome and metabolome changes consistent with impaired oxidative phosphorylation.
abstract: The diagnosis and management of drug-induced liver injury (DILI) is hindered by the limited utility of traditional clinical chemistries. It has recently been shown that hepatotoxicants can produce compound-specific changes in the peripheral blood (PB) transcriptome in rodents, suggesting that the blood transcriptome might provide new biomarkers of DILI. To investigate in humans, we used DNA microarrays as well as serum metabolomic methods to characterize changes in the transcriptome and metabolome in serial PB samples obtained from six healthy adults treated with a 4-g bolus dose of acetaminophen (APAP) and from three receiving placebo. Treatment did not cause liver injury as assessed by traditional liver chemistries. However, 48 hours after exposure, treated subjects showed marked down-regulation of genes involved in oxidative phosphorylation/mitochondrial function that was not observed in the placebos (P < 1.66E-19). The magnitude of down-regulation was positively correlated with the percent of APAP converted to the reactive metabolite N-acetyl-p-benzoquinone-imide (NAPQI) (r= 0.739;P= 0.058). In addition, unbiased analysis of the serum metabolome revealed an increase in serum lactate from 24 to 72 hours postdosing in the treated subjects alone (P< 0.005). Similar PB transcriptome changes were observed in human overdose patients and rats receiving toxic doses.
  
  
  CONCLUSIONS
  The single 4-g APAP dose produced a transcriptome signature in PB cells characterized by down-regulation of oxidative phosphorylation genes accompanied by increased serum lactate. Similar gene expression changes were observed in rats and several patients after consuming hepatotoxic doses of APAP. The timing of the changes and the correlation with NAPQI production are consistent with mechanisms known to underlie APAP hepatoxicity. These studies support the further exploration of the blood transcriptome for biomarkers of DILI.
authors.affiliation: National Institute of Environmental Health Sciences Microarray Group, National Institutes of Health (NIH), Research Triangle Park, NC 27709, USA.
authors.forename: Rick D
authors.initials: RD
authors.lastname: Fannin
authors.forename: Mark
authors.initials: M
authors.lastname: Russo
authors.forename: Thomas M
authors.initials: TM
authors.lastname: O'Connell
authors.forename: Kevin
authors.initials: K
authors.lastname: Gerrish
authors.forename: Jason H
authors.initials: JH
authors.lastname: Winnike
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Macdonald
authors.forename: Jack
authors.initials: J
authors.lastname: Newton
authors.forename: Shahid
authors.initials: S
authors.lastname: Malik
authors.forename: Stella O
authors.initials: SO
authors.lastname: Sieber
authors.forename: Joel
authors.initials: J
authors.lastname: Parker
authors.forename: Ruchir
authors.initials: R
authors.lastname: Shah
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
authors.forename: Richard S
authors.initials: RS
authors.lastname: Paules
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000652:urine; D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000503:physiopathology*; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006801:Humans; D008099:Liver / Q000378:metabolism; D055442:Metabolome / Q000187:drug effects*; D008875:Middle Aged; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010919:Placebos; D051381:Rats
chemical_list: D015415:Biomarkers; D010919:Placebos; D000082:Acetaminophen