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 Lau, Monica A. Valentovic

Research output: Contribution to journalArticle

11 Citations (Scopus)

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

Fingerprint

Oxidative stress
Acetaminophen
Methionine
Mass spectrometry
Mass Spectrometry
Oxidative Stress
Liver
Carbamyl Phosphate
Proteins
Mitochondrial Proteins
4-hydroxy-2-nonenal
Sarcosine Dehydrogenase
Body Weight
Protein Carbonylation
Carbonylation
Weights and Measures
Subcellular Fractions
Cytosol

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

S-adenosyl-l-methionine protection of acetaminophen mediated oxidative stress and identification of hepatic 4-hydroxynonenal protein adducts by mass spectrometry. / Brown, James Mike; Kuhlman, Christopher; Terneus, Marcus V.; Labenski, Matthew T.; Lamyaithong, Andre Benja; Ball, John G.; Lau, Serrine; Valentovic, Monica A.

In: Toxicology and Applied Pharmacology, Vol. 281, No. 2, 01.12.2014, p. 174-184.

Research output: Contribution to journalArticle

Brown, James Mike ; Kuhlman, Christopher ; Terneus, Marcus V. ; Labenski, Matthew T. ; Lamyaithong, Andre Benja ; Ball, John G. ; Lau, Serrine ; Valentovic, Monica A. / S-adenosyl-l-methionine protection of acetaminophen mediated oxidative stress and identification of hepatic 4-hydroxynonenal protein adducts by mass spectrometry. In: Toxicology and Applied Pharmacology. 2014 ; Vol. 281, No. 2. pp. 174-184.
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AU - Labenski, Matthew T.

AU - Lamyaithong, Andre Benja

AU - Ball, John G.

AU - Lau, Serrine

AU - Valentovic, Monica A.

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N2 - 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.

AB - 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.

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