title: Adaptation to acetaminophen exposure elicits major changes in expression and distribution of the hepatic proteome.
abstract: Acetaminophen overdose is the leading cause of acute liver failure. One dose of 10-15 g causes severe liver damage in humans, whereas repeated exposure to acetaminophen in humans and animal models results in autoprotection. Insight of this process is limited to select proteins implicated in acetaminophen toxicity and cellular defence. Here we investigate hepatic adaptation to acetaminophen toxicity from a whole proteome perspective, using quantitative mass spectrometry. In a rat model, we show the response to acetaminophen involves the expression of 30% of all proteins detected in the liver. Genetic ablation of a master regulator of cellular defence, NFE2L2, has little effect, suggesting redundancy in the regulation of adaptation. We show that adaptation to acetaminophen has a spatial component, involving a shift in regionalisation of CYP2E1, which may prevent toxicity thresholds being reached. These data reveal unexpected complexity and dynamic behaviour in the biological response to drug-induced liver injury.
authors.affiliation: MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: R
authors.initials: R
authors.lastname: Eakins
authors.affiliation: MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: J
authors.initials: J
authors.lastname: Walsh
authors.affiliation: Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK.
authors.forename: L
authors.initials: L
authors.lastname: Randle
authors.affiliation: MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: R E
authors.initials: RE
authors.lastname: Jenkins
authors.affiliation: Almirall S. A. R &D Centre, Barcelona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Schuppe-Koistinen
authors.affiliation: MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: C
authors.initials: C
authors.lastname: Rowe
authors.affiliation: MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: P
authors.initials: P
authors.lastname: Starkey Lewis
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, L69 7ZL, UK.
authors.forename: O
authors.initials: O
authors.lastname: Vasieva
authors.affiliation: AstraZeneca R &D, Innovative Medicines, Personalised Healthcare &Biomarkers, Translational Science Centre, Science for Life Laboratory, Solna, Sweden.
authors.forename: N
authors.initials: N
authors.lastname: Prats
authors.affiliation: MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: N
authors.initials: N
authors.lastname: Brillant
authors.affiliation: AstraZeneca R &D, Innovative Medicines, Personalised Healthcare &Biomarkers, Translational Science Centre, Science for Life Laboratory, Solna, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Auli
authors.affiliation: MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: M
authors.initials: M
authors.lastname: Bayliss
authors.affiliation: MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: S
authors.initials: S
authors.lastname: Webb
authors.affiliation: MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Rees
authors.affiliation: MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: N R
authors.initials: NR
authors.lastname: Kitteringham
authors.affiliation: MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: C E
authors.initials: CE
authors.lastname: Goldring
authors.affiliation: MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: B K
authors.initials: BK
authors.lastname: Park
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000222:Adaptation, Physiological / Q000187:drug effects*; D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020543:Proteome; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1