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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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Autores principales: Neumann, Elizabeth, Mehboob, Huma, Ramírez, Jacqueline, Mirkov, Snezana, Zhang, Min, Liu, Wanqing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110524/
https://www.ncbi.nlm.nih.gov/pubmed/27899892
http://dx.doi.org/10.3389/fphar.2016.00437
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author Neumann, Elizabeth
Mehboob, Huma
Ramírez, Jacqueline
Mirkov, Snezana
Zhang, Min
Liu, Wanqing
author_facet Neumann, Elizabeth
Mehboob, Huma
Ramírez, Jacqueline
Mirkov, Snezana
Zhang, Min
Liu, Wanqing
author_sort Neumann, Elizabeth
collection PubMed
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.
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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 Front Pharmacol 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.
spellingShingle Pharmacology
Neumann, Elizabeth
Mehboob, Huma
Ramírez, Jacqueline
Mirkov, Snezana
Zhang, Min
Liu, Wanqing
Age-Dependent Hepatic UDP-Glucuronosyltransferase Gene Expression and Activity in Children
title 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_short Age-Dependent Hepatic UDP-Glucuronosyltransferase Gene Expression and Activity in Children
title_sort age-dependent hepatic udp-glucuronosyltransferase gene expression and activity in children
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110524/
https://www.ncbi.nlm.nih.gov/pubmed/27899892
http://dx.doi.org/10.3389/fphar.2016.00437
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