S-adenosyl-l-methionine protection of acetaminophen mediated oxidative stress and identification of hepatic 4-hydroxynonenal protein adducts by mass spectrometry

James Mike Brown, Christopher Kuhlman, Marcus V. Terneus, Matthew T. Labenski, Andre Benja Lamyaithong, John G. Ball, Serrine S. Lau, Monica A. Valentovic

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Acetaminophen (APAP) hepatotoxicity is protected by S-adenosyl-. l-methionine (SAMe) treatment 1. hour (h) after APAP in C57/Bl6 mice. This study examined protein carbonylation as well as mitochondrial and cytosolic protein adduction by 4-hydroxynonenal (4-HNE) using mass spectrometry (MS) analysis. Additional studies investigated the leakage of mitochondrial proteins and 4-HNE adduction of these proteins. Male C57/Bl6 mice (n. = 5/group) were divided into the following groups and treated as indicated: Veh (15. ml/kg water, ip), SAMe (1.25. mmol/kg, ip), APAP (250. mg/kg), and SAMe given 1. h after APAP (S. +. A). APAP toxicity was confirmed by an increase (p. <. 0.05) in plasma ALT (U/l) and liver weight/10. g body weight relative to the Veh, SAMe and S. +. A groups 4. h following APAP treatment. SAMe administered 1. h post-APAP partially corrected APAP hepatotoxicity as ALT and liver weight/10. g body weights were lower in the S. +. A group compared the APAP group. APAP induced leakage of the mitochondrial protein, carbamoyl phosphate synthase-1 (CPS-1) into the cytosol and which was reduced in the S. +. A group. SAMe further reduced the extent of APAP mediated 4-HNE adduction of CPS-1. MS analysis of hepatic and mitochondrial subcellular fractions identified proteins from APAP treated mice. Site specific 4-HNE adducts were identified on mitochondrial proteins sarcosine dehydrogenase and carbamoyl phosphate synthase-1 (CPS-1). In summary, APAP is associated with 4-HNE adduction of proteins as identified by MS analysis and that CPS-1 leakage was greater in APAP treated mice. SAMe reduced the extent of 4-HNE adduction of proteins as well as leakage of CPS-1.

Original languageEnglish (US)
Pages (from-to)174-184
Number of pages11
JournalToxicology and Applied Pharmacology
Volume281
Issue number2
DOIs
StatePublished - Dec 1 2014

Keywords

  • 4-Hydroxynonenal
  • Acetaminophen
  • Hepatotoxicity
  • Mass spectrometry
  • Oxidative stress
  • Protein adduction

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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