Journal article
Transcriptome association analysis identifies miR-375 as a major determinant of variable acetaminophen glucuronidation by human liver
Biochemical pharmacology, Vol.117, pp.78-87
10/01/2016
Handle:
https://hdl.handle.net/2376/101870
PMCID: PMC5031542
PMID: 27531059
Abstract
[Display omitted]
Acetaminophen is the leading cause of acute liver failure (ALF) in many countries including the United States. Hepatic glucuronidation by UDP-glucuronosyltransferase (UGT) 1A subfamily enzymes is the major route of acetaminophen elimination. Reduced glucuronidation may predispose some individuals to acetaminophen-induced ALF, but mechanisms underlying reduced glucuronidation are poorly understood. We hypothesized that specific microRNAs (miRNAs) may reduce UGT1A activity by direct effects on the UGT1A 3′-UTR shared by all UGT1A enzyme transcripts, or by indirect effects on transcription factors regulating UGT1A expression. We performed an unbiased miRNA whole transcriptome association analysis using a bank of human livers with known acetaminophen glucuronidation activities. Of 754 miRNAs evaluated, 9 miRNAs were identified that were significantly overexpressed (p<0.05; >2-fold) in livers with low acetaminophen glucuronidation activities compared with those with high activities. miR-375 showed the highest difference (>10-fold), and was chosen for further mechanistic validation. We demonstrated using in silico analysis and luciferase reporter assays that miR-375 has a unique functional binding site in the 3′-UTR of the aryl hydrocarbon receptor (AhR) gene. Furthermore overexpression of miR-375 in LS180 cells demonstrated significant repression of endogenous AhR protein (by 40%) and mRNA (by 10%), as well as enzyme activity and/or mRNA of AhR regulated enzymes including UGT1A1, UGT1A6, and CYP1A2, without affecting UGT2B7, which is not regulated by AhR. Thus miR-375 is identified as a novel repressor of UGT1A-mediated hepatic acetaminophen glucuronidation through reduced AhR expression, which could predispose some individuals to increased risk for acetaminophen-induced ALF.
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Details
- Title
- Transcriptome association analysis identifies miR-375 as a major determinant of variable acetaminophen glucuronidation by human liver
- Creators
- Ioannis Papageorgiou - Program in Individualized Medicine (PrIMe), Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA, USAMarina Freytsis - Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USAMichael H Court - Program in Individualized Medicine (PrIMe), Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA, USA
- Publication Details
- Biochemical pharmacology, Vol.117, pp.78-87
- Academic Unit
- Veterinary Clinical Sciences, Department of
- Publisher
- Elsevier Inc
- Identifiers
- 99900546683101842
- Language
- English
- Resource Type
- Journal article