Archives of Toxicology

, Volume 88, Issue 2, pp 391–401 | Cite as

Circulating acylcarnitines as biomarkers of mitochondrial dysfunction after acetaminophen overdose in mice and humans

  • Mitchell R. McGill
  • Feng Li
  • Matthew R. Sharpe
  • C. David Williams
  • Steven C. Curry
  • Xiaochao Ma
  • Hartmut JaeschkeEmail author
Molecular Toxicology


Acetaminophen (APAP) is a widely used analgesic. However, APAP overdose is hepatotoxic and is the primary cause of acute liver failure in the developed world. The mechanism of APAP-induced liver injury begins with protein binding and involves mitochondrial dysfunction and oxidative stress. Recent efforts to discover blood biomarkers of mitochondrial damage have identified increased plasma glutamate dehydrogenase activity and mitochondrial DNA concentration in APAP overdose patients. However, a problem with these markers is that they are too large to be released from cells without cell death or loss of membrane integrity. Metabolomic studies are more likely to reveal biomarkers that are useful at early time points, before injury begins. Similar to earlier work, our metabolomic studies revealed that acylcarnitines are elevated in serum from mice after treatment with toxic doses of APAP. Importantly, a comparison with furosemide demonstrated that increased serum acylcarnitines are specific for mitochondrial dysfunction. However, when we measured these compounds in plasma from humans with liver injury after APAP overdose, we could not detect any significant differences from control groups. Further experiments with mice showed that N-acetylcysteine, the antidote for APAP overdose in humans, can reduce acylcarnitine levels in serum. Altogether, our data do not support the clinical measurement of acylcarnitines in blood after APAP overdose due to the standard N-acetylcysteine treatment in patients, but strongly suggest that acylcarnitines would be useful mechanistic biomarkers in other forms of liver injury involving mitochondrial dysfunction.


Acetaminophen toxicity Biomarkers Mitochondria Acylcarnitines 



Alanine aminotransferase




Carnitine-acylcarnitine translocase


Carnitine palmitoyltransferase


Glutamate dehydrogenase


c-Jun N-terminal kinase


Mixed lineage kinase 3


Mitochondrial membrane permeability transition


Mitochondrial DNA




N-acetyl-p-benzoquinone imine


Orthogonal projection to latent structures-discriminant analysis


Principal component analysis


Reactive oxygen species



This work was supported in part by Grants from McNeil Consumer Health Inc. (to H.J. and S.C.C.), by the University of Kansas Medical Center Liver Center (to H.J.), by the National Institutes of Health Grants R01 DK070195 and R01 AA12916 (to H.J.), and by Grants from the National Center for Research Resources (5P20RR021940-07) and the National Institute of General Medical Sciences (8 P20 GM103549-07) of the National Institutes of Health. Additional support came from an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant number P20 GM12345 and, from the “Training Program in Environmental Toxicology” T32 ES007079-26A2 (to M.R.M. and C.D.W.) from the National Institute of Environmental Health Sciences.

Conflict of interest

The authors declare no competing financial interest.

Supplementary material

204_2013_1118_MOESM1_ESM.docx (560 kb)
Supplementary material 1 (DOCX 560 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Mitchell R. McGill
    • 1
  • Feng Li
    • 1
  • Matthew R. Sharpe
    • 2
  • C. David Williams
    • 1
  • Steven C. Curry
    • 3
    • 4
  • Xiaochao Ma
    • 1
  • Hartmut Jaeschke
    • 1
    Email author
  1. 1.Department of Pharmacology, Toxicology, and TherapeuticsUniversity of Kansas Medical CenterKansas CityUSA
  2. 2.Department of Internal MedicineUniversity of Kansas HospitalKansas CityUSA
  3. 3.Department of Medical ToxicologyBanner Good Samaritan Medical CenterPhoenixUSA
  4. 4.Department of Medicine, Center for Toxicology and Pharmacology Education and ResearchUniversity of Arizona College of MedicinePhoenixUSA

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