title: Proteomic analysis of acetaminophen-induced changes in mitochondrial protein expression using spectral counting.
abstract: Comparative proteomic analysis following treatment with acetaminophen (APAP) was performed on two different models of APAP-mediated hepatocellular injury in order to both identify common targets for adduct formation and track drug-induced changes in protein expression. Male C57BL/6 mice were used as a model for APAP-mediated liver injury in vivo, and TAMH cells were used as a model for APAP-mediated cytotoxicity in vitro. SEQUEST was unable to identify the precise location of sites of adduction following treatment with APAP in either system. However, semiquantitative analysis of the proteomic data sets using spectral counting revealed a downregulation of P450 isoforms associated with APAP bioactivation and an upregulation of proteins related to the electron transport chain by APAP compared to the control. Both mechanisms are likely compensatory in nature as decreased P450 expression is likely to attenuate toxicity associated with N-acetyl-p-quinoneimine (NAPQI) formation, whereas APAP-induced electron transport chain component upregulation may be an attempt to promote cellular bioenergetics.
authors.affiliation: Departments of Medicinal Chemistry and Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, United States.
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Stamper
authors.forename: Isaac
authors.initials: I
authors.lastname: Mohar
authors.forename: Terrance J
authors.initials: TJ
authors.lastname: Kavanagh
authors.forename: Sidney D
authors.initials: SD
authors.lastname: Nelson
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D040901:Proteomics; D053719:Tandem Mass Spectrometry
chemical_list: D024101:Mitochondrial Proteins; D020033:Protein Isoforms; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System