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Arch Toxicol. 2018 Feb;92(2):845-858. doi: 10.1007/s00204-017-2090-y. Epub 2017 Oct 24.

Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans.

Author information

1
School of Public Health, Qingdao University, Qingdao, China.
2
National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
3
Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children's Research Institute, Little Rock, AR, USA.
4
Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China.
5
School of Pharmacy and School of Life Science, Fudan University, Shanghai, China.
6
School of Life Science, East Normal University, Shanghai, China.
7
Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children's Research Institute, Little Rock, AR, USA. JamesLauraP@uams.edu.
8
National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA. Weida.tong@fda.hhs.gov.
9
National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA. baitang.ning@fda.hhs.gov.

Abstract

Acetaminophen (APAP) overdose is the leading cause of acute liver failure. Yet the mechanisms underlying adaptive tolerance toward APAP-induced liver injury are not fully understood. To better understand molecular mechanisms contributing to adaptive tolerance to APAP is an underpinning foundation for APAP-related precision medicine. In the current study, the mRNA and microRNA (miRNA) expression profiles derived from next generation sequencing data for APAP-treated (5 and 10 mM) HepaRG cells and controls were analyzed systematically. Putative miRNAs targeting key dysregulated genes involved in APAP hepatotoxicity were selected using in silico prediction algorithms, un-biased gene ontology, and network analyses. Luciferase reporter assays, RNA electrophoresis mobility shift assays, and miRNA pull-down assays were performed to investigate the role of miRNAs affecting the expression of dysregulated genes. Levels of selected miRNAs were measured in serum samples obtained from children with APAP overdose (58.6-559.4 mg/kg) and from healthy controls. As results, 2758 differentially expressed genes and 47 miRNAs were identified. Four of these miRNAs (hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p) suppressed drug metabolizing enzyme (DME) levels involved in APAP-induced liver injury by downregulating HNF1A, HNF4A and NR1I2 expression. Exogenous transfection of these miRNAs into HepaRG cells effectively rescued them from APAP toxicity, as indicated by decreased alanine aminotransferase levels. Importantly, hsa-miR-320a and hsa-miR-877-5p levels were significantly elevated in serum samples obtained from children with APAP overdose compared to health controls. Collectively, these data indicate that hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p suppress DME expression involved in APAP-induced hepatotoxicity and they contribute to an adaptive response in hepatocytes.

KEYWORDS:

Acetaminophen; Adaptation; Drug metabolizing enzymes; MicroRNAs; Pharmacogenomics

PMID:
29067470
PMCID:
PMC5820133
DOI:
10.1007/s00204-017-2090-y
[Indexed for MEDLINE]
Free PMC Article

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