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Bhattacharyya S, Pence L, Beger R, et al. Acylcarnitine profiles in acetaminophen toxicity in the mouse: comparison to toxicity, metabolism and hepatocyte regeneration. Metabolites. 2013;3(3):606-22doi: 10.3390/metabo3030606.
Bhattacharyya, S., Pence, L., Beger, R., Chaudhuri, S., McCullough, S., Yan, K., Simpson, P., Hennings, L., Hinson, J., & James, L. (2013). Acylcarnitine profiles in acetaminophen toxicity in the mouse: comparison to toxicity, metabolism and hepatocyte regeneration. Metabolites, 3(3), 606-22. https://doi.org/10.3390/metabo3030606
Bhattacharyya, Sudeepa, et al. "Acylcarnitine profiles in acetaminophen toxicity in the mouse: comparison to toxicity, metabolism and hepatocyte regeneration." Metabolites vol. 3,3 (2013): 606-22. doi: https://doi.org/10.3390/metabo3030606
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 Aug 02;3(3):606-22. doi: 10.3390/metabo3030606. PMID: 24958141; PMCID: PMC3901280.
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Metabolites. 2013 Aug 02;3(3):606-22. doi: 10.3390/metabo3030606.

Acylcarnitine profiles in acetaminophen toxicity in the mouse: comparison to toxicity, metabolism and hepatocyte regeneration.

Metabolites

Sudeepa Bhattacharyya, Lisa Pence, Richard Beger, Shubhra Chaudhuri, Sandra McCullough, Ke Yan, Pippa Simpson, Leah Hennings, Jack Hinson, Laura James

Affiliations

  1. Departments of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA. [email protected].
  2. Division of Systems Biology, National Center for Toxicological Research, Jefferson, AR 72079, USA. [email protected].
  3. Division of Systems Biology, National Center for Toxicological Research, Jefferson, AR 72079, USA. [email protected].
  4. Departments of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA. [email protected].
  5. Departments of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA. [email protected].
  6. Medical College of Wisconsin, Milwaukee, WI 53226, USA. [email protected].
  7. Medical College of Wisconsin, Milwaukee, WI 53226, USA. [email protected].
  8. Departments of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. [email protected].
  9. Departments of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. [email protected].
  10. Departments of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA. [email protected].

PMID: 24958141 PMCID: PMC3901280 DOI: 10.3390/metabo3030606

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.

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