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

Metabolites

Sudeepa Bhattacharyya²  Lisa Pence⁵  Richard Beger⁵  Shubhra Chaudhuri²  Sandra McCullough²  Ke Yan⁴  Pippa Simpson⁴  Leah Hennings³  Jack Hinson¹ 

[1] Departments of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; E-Mail:;Departments of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA; E-Mails:;Departments of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; E-Mail:;Medical College of Wisconsin, Milwaukee, WI 53226, USA; E-Mails:;Division of Systems Biology, National Center for Toxicological Research, Jefferson, AR 72079, USA; E-Mails:

关键词: acetaminophen;    hepatic;    β-oxidation;    toxicity;    acylcarnitine;   

DOI  :  10.3390/metabo3030606

来源: mdpi

【 摘 要 】

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.

【 授权许可】

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© 2013 by the authors; licensee MDPI, Basel, Switzerland.