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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

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

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

Published In Toxicol Appl Pharmacol, (2014 Dec 01)

Abstract: Acetaminophen (APAP) hepatotoxicity is protected by S-adenosyl-l-methionine (SAMe) treatment 1hour (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 (15ml/kg water, ip), SAMe (1.25mmol/kg, ip), APAP (250mg/kg), and SAMe given 1h after APAP (S+A). APAP toxicity was confirmed by an increase (p<0.05) in plasma ALT (U/l) and liver weight/10g body weight relative to the Veh, SAMe and S+A groups 4h following APAP treatment. SAMe administered 1h post-APAP partially corrected APAP hepatotoxicity as ALT and liver weight/10g 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.

PubMed ID: 25246065 Exiting the NIEHS site

MeSH Terms: Acetaminophen*; Aldehydes/metabolism*; Animals; Antioxidants/pharmacology*; Carbamoyl-Phosphate Synthase (Ammonia)/metabolism; Chemical and Drug Induced Liver Injury/etiology; Chemical and Drug Induced Liver Injury/metabolism; Chemical and Drug Induced Liver Injury/prevention & control*; Chromatography, Liquid; Cytoprotection; Disease Models, Animal; Liver/drug effects*; Liver/metabolism; Male; Mice, Inbred BALB C; Mitochondria, Liver/drug effects; Mitochondria, Liver/metabolism; Oxidative Stress/drug effects*; Protein Carbonylation; Protein Processing, Post-Translational; S-Adenosylmethionine/pharmacology*; Sarcosine Dehydrogenase/metabolism; Tandem Mass Spectrometry*

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