Next Article in Journal
Tackling CASMI 2012: Solutions from MetFrag and MetFusion
Previous Article in Journal
Evaluation of Extraction Protocols for Simultaneous Polar and Non-Polar Yeast Metabolite Analysis Using Multivariate Projection Methods
Metabolites 2013, 3(3), 606-622; doi:10.3390/metabo3030606
Article

Acylcarnitine Profiles in Acetaminophen Toxicity in the Mouse: Comparison to Toxicity, Metabolism and Hepatocyte Regeneration

1,2
,
3
,
3
,
1,2
,
1,2
,
4
,
4
,
5
,
6
 and
1,6,*
1 Departments of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA 2 Arkansas Children's Hospital Research Institute, Little Rock, AR 72202 , USA 3 Division of Systems Biology, National Center for Toxicological Research, Jefferson, AR 72079, USA 4 Medical College of Wisconsin, Milwaukee, WI 53226, USA 5 Departments of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA 6 Departments of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
* Author to whom correspondence should be addressed.
Received: 16 April 2013 / Revised: 7 June 2013 / Accepted: 22 July 2013 / Published: 2 August 2013
View Full-Text   |   Download PDF [644 KB, 6 August 2013; original version 2 August 2013]   |  

Abstract

High doses of acetaminophen (APAP) result in hepatotoxicity that involves metabolic activation of the parent compound, covalent binding of the reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI) to liver proteins, and depletion of hepatic glutathione. Impaired fatty acid β-oxidation has been implicated in previous studies of APAP-induced hepatotoxicity. To better understand relationships between toxicity and fatty acid β-oxidation in the liver in APAP toxicity, metabolomic assays for long chain acylcarnitines were examined in relationship to established markers of liver toxicity, oxidative metabolism, and liver regeneration in a time course study in mice. Male B6C3F1 mice were treated with APAP (200 mg/kg IP) or saline and sacrificed at 1, 2, 4, 8, 24 or 48 h after APAP. At 1 h, hepatic glutathione was depleted and APAP protein adducts were markedly increased. Alanine aminotransferase (ALT) levels were elevated at 4 and 8 h, while proliferating cell nuclear antigen (PCNA) expression, indicative of hepatocyte regeneration, was apparent at 24 h and 48 h. Elevations of palmitoyl, oleoyl and myristoyl carnitine were apparent by 2–4 h, concurrent with the onset of Oil Red O staining in liver sections. By 8 h, acylcarnitine levels were below baseline levels and remained low at 24 and 48 h. A partial least squares (PLS) model suggested a direct association of acylcarnitine accumulation in serum to APAP protein adduct and hepatic glutathione levels in mice. Overall, the kinetics of serum acylcarnitines in APAP toxicity in mice followed a biphasic pattern involving early elevation after the metabolism phases of toxicity and later depletion of acylcarnitines.
Keywords: acetaminophen; hepatic; β-oxidation; toxicity; acylcarnitine acetaminophen; hepatic; β-oxidation; toxicity; acylcarnitine
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
SciFeed

Share & Cite This Article

Further Mendeley | CiteULike
Export to BibTeX |
EndNote |
RIS
MDPI and ACS Style

Bhattacharyya, S.; Pence, L.; Beger, R.; Chaudhuri, S.; McCullough, S.; Yan, K.; Simpson, P.; Hennings, L.; Hinson, J.; James, L. Acylcarnitine Profiles in Acetaminophen Toxicity in the Mouse: Comparison to Toxicity, Metabolism and Hepatocyte Regeneration. Metabolites 2013, 3, 606-622.

View more citation formats

Related Articles

Article Metrics

For more information on the journal, click here

Comments

[Return to top]
Metabolites EISSN 2218-1989 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert