Targeted liquid chromatography–mass spectrometry analysis of serum acylcarnitines in acetaminophen toxicity in children

Author:

Bhattacharyya Sudeepa1,Yan Ke2,Pence Lisa3,Simpson Pippa M2,Gill Pritmohinder1,Letzig Lynda G1,Beger Richard D3,Sullivan Janice E4,Kearns Gregory L5,Reed Michael D6,Marshall James D7,Van Den Anker John N8,James Laura P9

Affiliation:

1. Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA and Arkansas Children’s Hospital Research Institute, Little Rock, AR 72202, USA

2. Medical College of Wisconsin, Milwaukee, WI 53226, USA

3. Division of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA

4. Departments of Pediatrics & Pharmacology & Toxicology, Kosair Charities Pediatric Clinical Research Unit, University of Louisville, Louisville, KY 40202, USA and Kosair Children’s Hospital, Louisville, KY 40202, USA

5. Division of Pediatric Pharmacology, Medical Toxicology & Therapeutic Innovation, Children’s Mercy Hospital, Kansas City, MO 64108, USA

6. Division of Clinical Pharmacology & Toxicology, Department of Pediatrics, Northeast Ohio Medical University, Akron, OH 44038, USA and The Rebecca D Considine Research Institute, Akron Children’s Hospital, Akron, OH 44308, USA

7. Children’s Health Care System, Fort Worth, TX 76104, USA

8. Division of Pediatric Clinical Pharmacology, Children’s National Medical Center, Washington, DC 20010, USA

9. Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA and Arkansas Children’s Hospital Research Institute, Little Rock, AR 72202, USA and Departments of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

Abstract

Aim: Long-chain acylcarnitines have been postulated to be sensitive biomarkers of acetaminophen (APAP)-induced hepatotoxicity in mouse models. In the following study, the relationship of acylcarnitines with other known indicators of APAP toxicity was examined in children receiving low-dose (therapeutic) and high-dose (‘overdose’ or toxic ingestion) exposure to APAP. Materials & methods: The study included three subject groups: group A (therapeutic dose, n = 187); group B (healthy controls, n = 23); and group C (overdose, n = 62). Demographic, clinical and laboratory data were collected for each subject. Serum samples were used for measurement of APAP protein adducts, a biomarker of the oxidative metabolism of APAP and for targeted metabolomics analysis of serum acylcarnitines using ultra performance liquid chromatography–triple-quadrupole mass spectrometry. Results: Significant increases in oleoyl- and palmitoyl-carnitines were observed with APAP exposure (low dose and overdose) compared with controls. Significant increases in serum ALT, APAP protein adducts and acylcarnitines were observed in overdose children that received delayed treatment (time to treatment from overdose >24 h) with the antidote N-acetylcysteine. Time to peak APAP protein adducts in serum was shorter than that of the acylcarnitines and serum ALT. Conclusion: Perturbations in long-chain acylcarnitines in children with APAP toxicity suggest that mitochrondrial injury and associated impairment in the β-oxidation of fatty acids are clinically relevant as biomarkers of APAP toxicity.

Publisher

Future Medicine Ltd

Subject

Biochemistry, medical,Clinical Biochemistry,Drug Discovery

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