Journal article
Mitochondrial protein thiol modifications in acetaminophen hepatotoxicity: Effect on HMG-CoA synthase
Toxicology letters, Vol.177(3), pp.188-197
04/01/2008
DOI: 10.1016/j.toxlet.2008.01.010
PMCID: PMC2377066
PMID: 18313239
Abstract
Acetaminophen (APAP) overdose is the leading cause of drug related liver failure in many countries. N-acetyl-p-benzoquinone in-line (NAPQI) is a reactive metabolite that is formed by the metabolism of APAR NAPQI preferentially binds to glutathione and then cellular proteins. NAPQI binding is considered an upstream event in the pathophysiology, especially when binding to mitochondrial proteins and therefore leads to mitochondrial toxicity. APAP caused a significant increase in liver toxicity 3 h post-APAP administration as measured by increased serum alanine aminotransferase (ALT) levels. Using high-resolution mitochondrial proteomics techniques to measure thiol and protein changes, no significant change in global thiol levels was observed. However, 3-hydroxy-3-methylglutaryl coenzyme A synthase 2 (HMG-CoA synthase) had significantly decreased levels of reduced thiols and activity after APAP treatment. HMG-CoA synthase is a key regulatory enzyme in ketogenesis and possesses a number of critical cysteines in the active site. Similarly, catalase, a key enzyme in hydrogen peroxide metabolism, also showed modification in protein thiol content. These data indicate post-translational modifications of a few selected proteins involved in mitochondrial and cellular regulation of metabolism during liver toxicity after APAP overdose. The pathophysiological relevance of these limited changes in protein thiols remains to be investigated. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
Details
- Title: Subtitle
- Mitochondrial protein thiol modifications in acetaminophen hepatotoxicity: Effect on HMG-CoA synthase
- Creators
- Kelly K. Andringa - University of Alabama at BirminghamMary Lynn Bajt - University of Kansas Medical CenterHartmut Jaeschke - University of Kansas Medical CenterShannon M. Bailey - University of Alabama at Birmingham
- Resource Type
- Journal article
- Publication Details
- Toxicology letters, Vol.177(3), pp.188-197
- DOI
- 10.1016/j.toxlet.2008.01.010
- PMID
- 18313239
- PMCID
- PMC2377066
- NLM abbreviation
- Toxicol Lett
- ISSN
- 0378-4274
- eISSN
- 1879-3169
- Publisher
- Elsevier
- Number of pages
- 10
- Grant note
- P20 RR021940; P20 RR016475; P20 RR 021940 / NCRR NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) R01AA012916 / NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) R01 DK070195; R21 DK073775; DK070195; R21 DK073775-02 / NIDDK NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) R01 AA015172-04; R01 AA012916; R01 AA015172; R01 AA12916; R01 AA15172 / NIAAA NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) P20RR016475 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) R21DK073775 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)
- Language
- English
- Date published
- 04/01/2008
- Academic Unit
- Orthopedics and Rehabilitation
- Record Identifier
- 9984548671402771
Metrics
49 Record Views