title: Comparison of Bile Acids and Acetaminophen Protein Adducts in Children and Adolescents with Acetaminophen Toxicity.
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<0.001), glycodeoxycholic acid (R=0.581; p<0.001), and glycochenodeoxycholic acid (R=0.571; p<0.001). Variability in bile acids was greater among hospitalized children receiving low doses of acetaminophen than in healthy children with no recent acetaminophen exposure. Compared to bile acids, acetaminophen protein adducts more accurately discriminated among children with acetaminophen overdose, children with low dose exposure to acetaminophen, and healthy control subjects. In children with acetaminophen overdose, elevations of conjugated bile acids were associated with specific indicators of acetaminophen metabolism and non-specific indicators of liver injury.
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, United States of America; Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, United States of America.
authors.forename: Laura
authors.initials: L
authors.lastname: James
authors.affiliation: Medical College of Wisconsin, Milwaukee, WI 53226, United States of America.
authors.forename: Ke
authors.initials: K
authors.lastname: Yan
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Jefferson, AR 72079, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Pence
authors.affiliation: Medical College of Wisconsin, Milwaukee, WI 53226, United States of America.
authors.forename: Pippa
authors.initials: P
authors.lastname: Simpson
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, United States of America; Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, United States of America.
authors.forename: Sudeepa
authors.initials: S
authors.lastname: Bhattacharyya
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, United States of America; Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, United States of America.
authors.forename: Pritmohinder
authors.initials: P
authors.lastname: Gill
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, United States of America; Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, United States of America.
authors.forename: Lynda
authors.initials: L
authors.lastname: Letzig
authors.affiliation: Division of Pediatric Pharmacology, Medical Toxicology and Therapeutic Innovation, The Children's Mercy Hospital, Kansas City, MO 64108, United States of America.
authors.forename: Gregory
authors.initials: G
authors.lastname: Kearns
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Jefferson, AR 72079, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Beger
mesh_terms: D000082:Acetaminophen / Q000378:metabolism / Q000506:poisoning*; D000293:Adolescent; D000410:Alanine Transaminase / Q000378:metabolism; D001647:Bile Acids and Salts / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000175:diagnosis; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D062787:Drug Overdose / Q000097:blood* / Q000175:diagnosis; D005260:Female; D005999:Glycochenodeoxycholic Acid / Q000097:blood; D006002:Glycodeoxycholic Acid / Q000097:blood; D006706:Homeostasis; D006801:Humans; D008297:Male; D055432:Metabolomics / Q000379:methods; D011485:Protein Binding; D012680:Sensitivity and Specificity; D013657:Taurodeoxycholic Acid / Q000097:blood
chemical_list: D001647:Bile Acids and Salts; D015415:Biomarkers; D006002:Glycodeoxycholic Acid; D000082:Acetaminophen; D013657:Taurodeoxycholic Acid; D005999:Glycochenodeoxycholic Acid; D000410:Alanine Transaminase