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 language | English (US) |
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Pages (from-to) | 174-184 |
Number of pages | 11 |
Journal | Toxicology and Applied Pharmacology |
Volume | 281 |
Issue number | 2 |
DOIs | |
State | Published - Dec 1 2014 |
Externally published | Yes |
Keywords
- 4-Hydroxynonenal
- Acetaminophen
- Hepatotoxicity
- Mass spectrometry
- Oxidative stress
- Protein adduction
ASJC Scopus subject areas
- Toxicology
- Pharmacology