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, 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.

Characterization of the Ontogeny of Hepatic UDP‐Glucuronosyltransferase Enzymes Based on Glucuronidation Activity Measured in Human Liver Microsomes

“…14 To date, the ontogeny of 7 hepatic UGT isoforms (UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B15, and UGT2B17) has been evaluated based on glucuronidation activity or protein abundance determined in human liver microsomes (HLMs) in independent studies. [15][16][17][18][19][20][21][22][23] In addition, protein abundance-activity correlations for those UGT isoforms was demonstrated recently by Bhatt et al 22 Distinct maturation of activity or protein expression levels between those UGT isoforms and across different age categories were demonstrated with maximum UGT-mediated metabolic capacity achieved at different times after birth. 5,21,22 The ontogeny pattern of other major hepatic UGT isoforms, including UGT1A3, UGT2B4, and UGT2B10, remained to be elucidated.…”

“…To date, the ontogeny of 7 hepatic UGT isoforms (UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B15, and UGT2B17) has been evaluated based on glucuronidation activity or protein abundance determined in human liver microsomes (HLMs) in independent studies . In addition, protein abundance‐activity correlations for those UGT isoforms was demonstrated recently by Bhatt et al .…”

A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model of the histone deacetylase (HDAC) inhibitor vorinostat for pediatric and adult patients and its application for dose specification

“…The age-dependent maturation of UGT 1A9 and 2B7 was already available in PK-Sim, whereas the UGT 2B17 maturation was implemented using a Hill function (equation 1) based on recently published mRNA data [14], $$\mathrm{UGT}2\mathrm{B}17\text{ontogeny factor}(\mathrm{OF})={\mathrm{OF}}_{\min }+\frac{{\mathrm{OF}}_{\max }\ast {\text{Age}}^{\gamma }}{{{\mathrm{OF}}^{\gamma }}_{50}+{\text{Age}}^{\gamma }}$$ where OF min denotes the intercept with the y-axis and OF max and OF 50 represent the maximum adult ontogeny factor (= 1) and the post-menstrual age needed to reach 50% of the maximum ontogeny factor, respectively. Age denotes the post-menstrual age in years and γ denotes the Hill factor.…”

“…While the UDP-glucuronosyltransferases (UGTs) 1A9, 2B7, and 2B17 are the major enzymes of vorinostat glucuronidation, the enzyme responsible for hydrolysis and β-oxidation remains unidentified [7]. These enzymes exhibit nonlinear age-dependent maturations completed within 10 years after birth [9-14]. Genetic polymorphisms of UGT 2B17 might play a role in the clearance of vorinostat and in clinical outcomes [15-17].…”

Metabolic Profiling of the Novel Hypoxia-Inducible Factor 2α Inhibitor PT2385 In Vivo and In Vitro

“…It was also reported that UGT2B17 exhibited high expression in jejunum of morbidly obese subjects, and had the high inter-individual variation, which might be the result of genetic polymorphism (Miyauchi et al, 2016). Furthermore, the activity of UGT2B17 is also significantly impacted by complex factors, such as age, hormonal signaling, medications, supplements, alcohol consumption, and smoking (Neumann et al, 2016). Therefore, there might be significant inter-patient variability in drug metabolism in populations and drug-drug interactions of PT2385, and perhaps leading to increased toxicity or altered efficacy.…”