title: Acylcarnitine profiles in acetaminophen toxicity in the mouse: comparison to toxicity, metabolism and hepatocyte regeneration.
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.
authors: Departments of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA. SBhattacharyya2@uams.edu.
authors: Sudeepa
authors: S
authors: Bhattacharyya
authors: Division of Systems Biology, National Center for Toxicological Research, Jefferson, AR 72079, USA. Lisa.Pence@fda.hhs.gov.
authors: Lisa
authors: L
authors: Pence
authors: Division of Systems Biology, National Center for Toxicological Research, Jefferson, AR 72079, USA. Richard.beger@fda.hhs.gov.
authors: Richard
authors: R
authors: Beger
authors: Departments of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA. chaudhurishubhra@uams.edu.
authors: Shubhra
authors: S
authors: Chaudhuri
authors: Departments of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA. mcculloughsandras@uams.edu.
authors: Sandra
authors: S
authors: McCullough
authors: Medical College of Wisconsin, Milwaukee, WI 53226, USA. kyan@mcw.edu.
authors: Ke
authors: K
authors: Yan
authors: Medical College of Wisconsin, Milwaukee, WI 53226, USA. psimpson@mcw.edu.
authors: Pippa
authors: P
authors: Simpson
authors: Departments of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. lhennings@uams.edu.
authors: Leah
authors: L
authors: Hennings
authors: Departments of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. hinsonjacka@uams.edu.
authors: Jack
authors: J
authors: Hinson
authors: Departments of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA. jameslaurap@uams.edu.
authors: Laura
authors: L
authors: James