title: Age-Dependent Hepatic UDP-Glucuronosyltransferase Gene Expression and Activity in Children.
abstract: 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, andUGT2B17) and 16 transcription factors (AHR, AR, CAR, ESR2, FXR, GCCR, HNF1a, HNF3a, HNF3b, HNF4a, PPARA, PPARG, PPARGC, PXR, SP1, andSTAT3) 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 (nominalp< 0.05) in the expression ofUGT1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A6,UGT2B7, andUGT2B17, 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 andUGTmRNA expression (p≤ 0.05). These results suggest that bothUGTexpression 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.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University West Lafayette, IN, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Neumann
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue UniversityWest Lafayette, IN, USA; Department of Biochemistry, University of AgricultureFaisalabad, Pakistan.
authors.forename: Huma
authors.initials: H
authors.lastname: Mehboob
authors.affiliation: Section of Hematology and Oncology, Department of Medicine, The University of Chicago Chicago, IL, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ramírez
authors.affiliation: Section of Hematology and Oncology, Department of Medicine, The University of Chicago Chicago, IL, USA.
authors.forename: Snezana
authors.initials: S
authors.lastname: Mirkov
authors.affiliation: Department of Statistics, College of Science, Purdue UniversityWest Lafayette, IN, USA; Beijing Institute for Brain Disorders, Capital Medical UniversityBeijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University West Lafayette, IN, USA.
authors.forename: Wanqing
authors.initials: W
authors.lastname: Liu
keywords: UDP-glucuronosyltransferase; age; children; liver; ontogeny