title: Circulating acylcarnitines as biomarkers of mitochondrial dysfunction after acetaminophen overdose in mice and humans.
abstract: 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.
authors: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA.
authors: Mitchell R
authors: MR
authors: McGill
authors: Feng
authors: F
authors: Li
authors: Matthew R
authors: MR
authors: Sharpe
authors: C David
authors: CD
authors: Williams
authors: Steven C
authors: SC
authors: Curry
authors: Xiaochao
authors: X
authors: Ma
authors: Hartmut
authors: H
authors: Jaeschke
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000097:blood; D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood*; D002331:Carnitine / Q000031:analogs & derivatives* / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000473:pathology; D062787:Drug Overdose / Q000097:blood*; D006801:Humans; D008297:Male; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000931:Antidotes; D015415:Biomarkers; C116917:acylcarnitine; D000082:Acetaminophen; D002331:Carnitine; D000111:Acetylcysteine
references: J Biol Chem. 2011 Oct 7;286(40):35071-8
references: 21844199
references: Evid Based Complement Alternat Med. 2013;2013:985257
references: 23431354
references: JAMA. 2002 Jan 16;287(3):337-44
references: 11790213
references: Toxicol Appl Pharmacol. 2010 Jul;246(1-2):8-17
references: 20423716
references: Chem Res Toxicol. 2009 Apr;22(4):699-707
references: 19256530
references: Drug Metab Rev. 2012 Feb;44(1):88-106
references: 22229890
references: Annu Rev Physiol. 2002;64:477-502
references: 11826276
references: J Pharmacol Exp Ther. 2003 Oct;307(1):67-73
references: 12954812
references: Hepatology. 2013 Aug;58(2):777-87
references: 23390034
references: J Pharmacol Exp Ther. 1973 Oct;187(1):211-7
references: 4746329
references: Toxicol Sci. 2011 Aug;122(2):598-605
references: 21572097
references: Hepatology. 2010 Jan;51(1):246-54
references: 19821517
references: Toxicol Sci. 2013 Jul;134(1):221-2
references: 23568080
references: J Biol Chem. 2008 May 16;283(20):13565-77
references: 18337250
references: J Pharmacol Exp Ther. 1990 Dec;255(3):935-41
references: 2262912
references: Toxicol Lett. 2000 Aug 16;116(3):171-81
references: 10996478
references: Gastroenterology. 2008 Oct;135(4):1311-21
references: 18700144
references: Toxicol Appl Pharmacol. 2011 Mar 15;251(3):226-33
references: 21241727
references: Pharm Res. 2013 Sep;30(9):2174-87
references: 23462933
references: Proc Natl Acad Sci U S A. 1984 Mar;81(5):1327-31
references: 6424115
references: Mol Pharmacol. 2012 Nov;82(5):1001-7
references: 22918968
references: Hepatology. 2011 Mar;53(3):974-82
references: 21319200
references: J Clin Invest. 2012 Apr;122(4):1574-83
references: 22378043
references: Toxicol Sci. 2004 Aug;80(2):343-9
references: 15115886
references: Clin Sci Mol Med. 1975 Nov;49(5):495-502
references: 1192708
references: J Pharmacol Exp Ther. 2002 Nov;303(2):468-75
references: 12388625
references: J Biol Chem. 1989 Jun 15;264(17):9814-9
references: 2524496
references: Gastroenterology. 2006 Jul;131(1):165-78
references: 16831600
references: Toxicol Sci. 2006 Nov;94(1):217-25
references: 16896059
references: Toxicol Appl Pharmacol. 2013 Jun 15;269(3):240-9
references: 23571099
references: Gastroenterology. 2006 Mar;130(3):687-94
references: 16530510
references: J Hepatol. 1987 Apr;4(2):206-11
references: 3584929
references: Hepatology. 2004 Nov;40(5):1170-9
references: 15486922
references: J Pharmacol Exp Ther. 2005 Nov;315(2):879-87
references: 16081675
references: J Pharmacol Exp Ther. 2008 Jan;324(1):8-14
references: 17906064
references: Toxicology. 1981;19(2):113-25
references: 7268784