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Cytokines and Toxicity in Acetaminophen Overdose

From the Departments of Pediatrics (Dr James, Dr Simpson, Dr Farrar) and Pharmacology (Dr James, Dr Hinson), University of Arkansas for Medical Sciences and Arkansas Children's Hospital (Dr James, Dr Simpson, Dr Farrar), Little Rock, Arkansas; Departments of Pediatrics (Dr Kearns, Dr Wasserman) and Pharmacology (Dr Kearns), University of Missouri–Kansas City, Division of Pediatric Clinical Pharmacology and Medical Toxicology (Dr Kearns, Dr Wasserman), The Children's Mercy Hospitals and Clinics, Kansas City, Missouri; Department of Pediatrics and Pharmacology (Dr Blumer, Dr Reed), Case Western Reserve University, and the Division of Pediatric Pharmacology and Critical Care Medicine, Rainbow Babies and Children's Hospital, Cleveland, Ohio (Dr Blumer, Dr Reed); Departments of Pediatrics and Pharmacology/Toxicology, University of Louisville and Kosair Children's Hospital, Louisville, Kentucky (Dr Sullivan); and the National Institute of Child Health and Human Development, Bethesda, Maryland (The Pediatric Pharmacology Research Unit Network).

Several cytokines have been reported to have hepatoprotective properties in animal models of acetaminophen toxicity. To investigate the relationships of cytokines and toxicity in acetaminophen overdose, blood samples were collected from patients following acute ingestions of acetaminophen. Samples for cytokine analysis were collected at the time of routine clinical monitoring in 111 patients (90 females; mean age 13.6 years). Plasma concentrations of interleukin 6, interleukin 8, interleukin 10, and monocyte chemoattractant protein 1 were analyzed by enzyme-linked immunosorbent assay. Patients were stratified by toxicity severity, defined by the maximal values of hepatic transaminase elevation. Levels of interleukin 6, interleukin 8, and monocyte chemoattractant protein 1 were higher in patients with serum alanine aminotransferase > 1000 IU/L, and monocyte chemoattractant protein 1 had the strongest association with toxicity. Monocyte chemoattractant protein 1 values were higher in patients with greater delays in N-acetylcysteine treatment and in patients with higher values of prothrombin time. Monocyte chemoattractant protein 1 elevation in acetaminophen overdose may represent an innate, immunomodulary response of the liver to earlier events in the toxicity. An understanding of the role of cytokine responses in acetaminophen overdose may be relevant to the future development of new therapies for acetaminophen toxicity.

Key Words: Acetaminophen • cytokines • monocyte chemoattractant protein 1

Address for reprints: Laura P. James, MD, Department of Pediatrics, Section of Clinical Pharmacology and Toxicology, Arkansas Children's Hospital, 800 Marshall Street, Little Rock, AR 72202; e-mail: Jameslaurap{at}uams.edu.

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