Age-Dependent Hepatic UDP-Glucuronosyltransferase Gene Expression and Activity in Children

Age-Dependent Hepatic UDP-Glucuronosyltransferase Gene Expression and Activity in Children

UDP-glucuronosyltransferases (UGTs) are important phase II drug metabolism enzymes. The aim of this study was to explore the relationship between age and changes in mRNA expression and activity of major human hepatic UGTs, as well as to understand the potential regulatory mechanism underlying this r...

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Main Authors: Neumann, Elizabeth, Mehboob, Huma, Ramírez, Jacqueline, Mirkov, Snezana, Zhang, Min, Liu, Wanqing
Format: Online
Language:English
Published: Frontiers Media S.A. 2016
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110524/
id pubmed-5110524
recordtype oai_dc
spelling pubmed-51105242016-11-29 Age-Dependent Hepatic UDP-Glucuronosyltransferase Gene Expression and Activity in Children Neumann, Elizabeth Mehboob, Huma Ramírez, Jacqueline Mirkov, Snezana Zhang, Min Liu, Wanqing Pharmacology UDP-glucuronosyltransferases (UGTs) are important phase II drug metabolism enzymes. The aim of this study was to explore the relationship between age and changes in mRNA expression and activity of major human hepatic UGTs, as well as to understand the potential regulatory mechanism underlying this relationship. Using previously generated data, we investigated age-dependent mRNA expression levels of 11 hepatic UGTs (UGT1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B10, UGT2B15, and UGT2B17) and 16 transcription factors (AHR, AR, CAR, ESR2, FXR, GCCR, HNF1a, HNF3a, HNF3b, HNF4a, PPARA, PPARG, PPARGC, PXR, SP1, and STAT3) in liver tissue of donors (n = 38) ranging from 0 to 25 years of age. We also examined the correlation between age and microsomal activities using 14 known UGT drug substrates in the liver samples (n = 19) of children donors. We found a statistically significant increase (nominal p < 0.05) in the expression of UGT1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT2B7, and UGT2B17, as well as glucuronidation activities of serotonin, testosterone, and vorinostat during the first 25 years of life. Expression of estrogen receptor 1 and pregnane X receptor, two strong UGT transcriptional regulators, were significantly correlated with both age and UGT mRNA expression (p ≤ 0.05). These results suggest that both UGT expression and activity increase during childhood and adolescence, possibly driven in part by hormonal signaling. Our findings may help explain inter-patient variability in response to medications among children. Frontiers Media S.A. 2016-11-16 /pmc/articles/PMC5110524/ /pubmed/27899892 http://dx.doi.org/10.3389/fphar.2016.00437 Text en Copyright © 2016 Neumann, Mehboob, Ramírez, Mirkov, Zhang and Liu. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Neumann, Elizabeth
Mehboob, Huma
Ramírez, Jacqueline
Mirkov, Snezana
Zhang, Min
Liu, Wanqing
spellingShingle Neumann, Elizabeth
Mehboob, Huma
Ramírez, Jacqueline
Mirkov, Snezana
Zhang, Min
Liu, Wanqing
Age-Dependent Hepatic UDP-Glucuronosyltransferase Gene Expression and Activity in Children
author_facet Neumann, Elizabeth
Mehboob, Huma
Ramírez, Jacqueline
Mirkov, Snezana
Zhang, Min
Liu, Wanqing
author_sort Neumann, Elizabeth
title Age-Dependent Hepatic UDP-Glucuronosyltransferase Gene Expression and Activity in Children
title_short Age-Dependent Hepatic UDP-Glucuronosyltransferase Gene Expression and Activity in Children
title_full Age-Dependent Hepatic UDP-Glucuronosyltransferase Gene Expression and Activity in Children
title_fullStr Age-Dependent Hepatic UDP-Glucuronosyltransferase Gene Expression and Activity in Children
title_full_unstemmed Age-Dependent Hepatic UDP-Glucuronosyltransferase Gene Expression and Activity in Children
title_sort age-dependent hepatic udp-glucuronosyltransferase gene expression and activity in children
description UDP-glucuronosyltransferases (UGTs) are important phase II drug metabolism enzymes. The aim of this study was to explore the relationship between age and changes in mRNA expression and activity of major human hepatic UGTs, as well as to understand the potential regulatory mechanism underlying this relationship. Using previously generated data, we investigated age-dependent mRNA expression levels of 11 hepatic UGTs (UGT1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B10, UGT2B15, and UGT2B17) and 16 transcription factors (AHR, AR, CAR, ESR2, FXR, GCCR, HNF1a, HNF3a, HNF3b, HNF4a, PPARA, PPARG, PPARGC, PXR, SP1, and STAT3) in liver tissue of donors (n = 38) ranging from 0 to 25 years of age. We also examined the correlation between age and microsomal activities using 14 known UGT drug substrates in the liver samples (n = 19) of children donors. We found a statistically significant increase (nominal p < 0.05) in the expression of UGT1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT2B7, and UGT2B17, as well as glucuronidation activities of serotonin, testosterone, and vorinostat during the first 25 years of life. Expression of estrogen receptor 1 and pregnane X receptor, two strong UGT transcriptional regulators, were significantly correlated with both age and UGT mRNA expression (p ≤ 0.05). These results suggest that both UGT expression and activity increase during childhood and adolescence, possibly driven in part by hormonal signaling. Our findings may help explain inter-patient variability in response to medications among children.
publisher Frontiers Media S.A.
publishDate 2016
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110524/
_version_ 1613728168795963392

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