title: Potential of extracellular microRNAs as biomarkers of acetaminophen toxicity in children.
abstract: Developing biomarkers for detecting acetaminophen (APAP) toxicity has been widely investigated. Recent studies of adults with APAP-induced liver injury have reported human serum microRNA-122 (miR-122) as a novel biomarker of APAP-induced liver injury. The goal of this study was to examine extracellular microRNAs (miRNAs) as potential biomarkers for APAP liver injury in children. Global levels of serum and urine miRNAs were examined in three pediatric subgroups: 1) healthy children (n=10), 2) hospitalized children receiving therapeutic doses of APAP (n=10) and 3) children hospitalized for APAP overdose (n=8). Out of 147 miRNAs detected in the APAP overdose group, eight showed significantly increased median levels in serum (miR-122, -375, -423-5p, -30d-5p, -125b-5p, -4732-5p, -204-5p, and -574-3p), compared to the other groups. Analysis of urine samples from the same patients had significantly increased median levels of four miRNAs (miR-375, -940, -9-3p and -302a) compared to the other groups. Importantly, correlation of peak serum APAP protein adduct levels (an indicator of the oxidation of APAP to the reactive metabolite N-acetyl-para-quinone imine) with peak miRNA levels showed that the highest correlation was observed for serum miR-122 (R=0.94; p<0.01) followed by miR-375 (R=0.70; p=0.05).
  
  
  CONCLUSIONS
  Our findings demonstrate that miRNAs are increased in children with APAP toxicity and correlate with APAP protein adducts, suggesting a potential role as biomarkers of APAP toxicity.
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, USA. Electronic address: Xi.Yang@fda.hhs.gov.
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, USA. Electronic address: Willie.Salminen@parexel.com.
authors.forename: William F
authors.initials: WF
authors.lastname: Salminen
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, USA. Electronic address: Qiang.Shi@fda.hhs.gov.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, USA. Electronic address: James.Greenhaw@fda.hhs.gov.
authors.forename: James
authors.initials: J
authors.lastname: Greenhaw
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Clinical Pharmacology and Toxicology Section, Arkansas Children's Hospital, Little Rock, AR, USA. Electronic address: PSGill@uams.edu.
authors.forename: Pritmohinder S
authors.initials: PS
authors.lastname: Gill
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Clinical Pharmacology and Toxicology Section, Arkansas Children's Hospital, Little Rock, AR, USA. Electronic address: SBhattacharyya2@uams.edu.
authors.forename: Sudeepa
authors.initials: S
authors.lastname: Bhattacharyya
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, USA. Electronic address: Richard.Beger@fda.hhs.gov.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Beger
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, USA. Electronic address: Donna.Mendrick@fda.hhs.gov.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Mendrick
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, USA. Electronic address: William.Mattes@fda.hhs.gov.
authors.forename: William B
authors.initials: WB
authors.lastname: Mattes
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Clinical Pharmacology and Toxicology Section, Arkansas Children's Hospital, Little Rock, AR, USA. Electronic address: jameslaurap@uams.edu.
authors.forename: Laura P
authors.initials: LP
authors.lastname: James
mesh_terms: D000082:Acetaminophen / Q000378:metabolism / Q000506:poisoning*; D000293:Adolescent; D015415:Biomarkers / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D062787:Drug Overdose / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D000082:Acetaminophen
keywords: Acetaminophen; DILI; MicroRNA; Pediatric; Urine