RESEARCH ARTICLE
Comparison of Bile Acids and Acetaminophen Protein Adducts in Children and Adolescents with Acetaminophen Toxicity Laura James1,2*, Ke Yan3, Lisa Pence4, Pippa Simpson3, Sudeepa Bhattacharyya1,2, Pritmohinder Gill1,2, Lynda Letzig1,2, Gregory Kearns5, Richard Beger4 1 Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, United States of America, 2 Arkansas Children’s Hospital Research Institute, Little Rock, AR 72202, United States of America, 3 Medical College of Wisconsin, Milwaukee, WI 53226, United States of America, 4 Division of Systems Biology, National Center for Toxicological Research, Jefferson, AR 72079, United States of America, 5 Division of Pediatric Pharmacology, Medical Toxicology and Therapeutic Innovation, The Children’s Mercy Hospital, Kansas City, MO 64108, United States of America * [email protected] OPEN ACCESS Citation: James L, Yan K, Pence L, Simpson P, Bhattacharyya S, Gill P, et al. (2015) Comparison of Bile Acids and Acetaminophen Protein Adducts in Children and Adolescents with Acetaminophen Toxicity. PLoS ONE 10(7): e0131010. doi:10.1371/ journal.pone.0131010 Editor: Gustavo Batista Menezes, UFMG, BRAZIL Received: February 19, 2015 Accepted: May 26, 2015 Published: July 24, 2015 Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Data Availability Statement: All relevant data are available via Figshare (http://dx.doi.org/10.6084/m9. figshare.1412829). Funding: This work was funded in part by a grant (DK75936 to LJ) from the National Institutes of Diabetes, Digestive and Kidney Diseases of the United States Department of Health and Human Services and the Arkansas Biosciences Institute which is funded by Arkansas Tobacco Settlement Funds.
Abstract Metabolomics approaches have enabled the study of new mechanisms of liver injury in experimental models of drug toxicity. Disruption of bile acid homeostasis is a known mechanism of drug induced liver injury. The relationship of individual bile acids to indicators of oxidative drug metabolism (acetaminophen protein adducts) and liver injury was examined in children with acetaminophen overdose, hospitalized children with low dose exposure to acetaminophen, and children with no recent exposure to acetaminophen. Nine bile acids were quantified through targeted metabolomic analysis in the serum samples of the three groups. Bile acids were compared to serum levels of acetaminophen protein adducts and alanine aminotransferase. Glycodeoxycholic acid, taurodeoxycholic acid, and glycochenodeoxycholic acid were significantly increased in children with acetaminophen overdose compared to healthy controls. Among patients with acetaminophen overdose, bile acids were higher in subjects with acetaminophen protein adduct values > 1.0 nmol/mL and modest correlations were noted for three bile acids and acetaminophen protein adducts as follows: taurodeoxycholic acid (R=0.604; p
Comparison of Bile Acids and Acetaminophen Protein Adducts in Children and Adolescents with Acetaminophen Toxicity Laura James1,2*, Ke Yan3, Lisa Pence4, Pippa Simpson3, Sudeepa Bhattacharyya1,2, Pritmohinder Gill1,2, Lynda Letzig1,2, Gregory Kearns5, Richard Beger4 1 Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, United States of America, 2 Arkansas Children’s Hospital Research Institute, Little Rock, AR 72202, United States of America, 3 Medical College of Wisconsin, Milwaukee, WI 53226, United States of America, 4 Division of Systems Biology, National Center for Toxicological Research, Jefferson, AR 72079, United States of America, 5 Division of Pediatric Pharmacology, Medical Toxicology and Therapeutic Innovation, The Children’s Mercy Hospital, Kansas City, MO 64108, United States of America * [email protected] OPEN ACCESS Citation: James L, Yan K, Pence L, Simpson P, Bhattacharyya S, Gill P, et al. (2015) Comparison of Bile Acids and Acetaminophen Protein Adducts in Children and Adolescents with Acetaminophen Toxicity. PLoS ONE 10(7): e0131010. doi:10.1371/ journal.pone.0131010 Editor: Gustavo Batista Menezes, UFMG, BRAZIL Received: February 19, 2015 Accepted: May 26, 2015 Published: July 24, 2015 Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Data Availability Statement: All relevant data are available via Figshare (http://dx.doi.org/10.6084/m9. figshare.1412829). Funding: This work was funded in part by a grant (DK75936 to LJ) from the National Institutes of Diabetes, Digestive and Kidney Diseases of the United States Department of Health and Human Services and the Arkansas Biosciences Institute which is funded by Arkansas Tobacco Settlement Funds.
Abstract Metabolomics approaches have enabled the study of new mechanisms of liver injury in experimental models of drug toxicity. Disruption of bile acid homeostasis is a known mechanism of drug induced liver injury. The relationship of individual bile acids to indicators of oxidative drug metabolism (acetaminophen protein adducts) and liver injury was examined in children with acetaminophen overdose, hospitalized children with low dose exposure to acetaminophen, and children with no recent exposure to acetaminophen. Nine bile acids were quantified through targeted metabolomic analysis in the serum samples of the three groups. Bile acids were compared to serum levels of acetaminophen protein adducts and alanine aminotransferase. Glycodeoxycholic acid, taurodeoxycholic acid, and glycochenodeoxycholic acid were significantly increased in children with acetaminophen overdose compared to healthy controls. Among patients with acetaminophen overdose, bile acids were higher in subjects with acetaminophen protein adduct values > 1.0 nmol/mL and modest correlations were noted for three bile acids and acetaminophen protein adducts as follows: taurodeoxycholic acid (R=0.604; p
