Age- and Genotype-Dependent Variability in the Protein Abundance and Activity of Six Major Uridine Diphosphate-Glucuronosyltransferases in Human Liver.

Document Type

Article

Publication Date

1-2019

Identifier

DOI: 10.1002/cpt.1109; PMCID: PMC6222000

Abstract

The ontogeny of hepatic uridine diphosphate-glucuronosyltransferases (UGTs) was investigated by determining their protein abundance in human liver microsomes isolated from 136 pediatric (0-18 years) and 35 adult (age >18 years) donors using liquid chromatography / tandem mass spectrometry (LC-MS/MS) proteomics. Microsomal protein abundances of UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 increased by ∼8, 55, 35, 33, 8, and 3-fold from neonates to adults, respectively. The estimated age at which 50% of the adult protein abundance is observed for these UGT isoforms was between 2.6-10.3 years. Measured in vitro activity was generally consistent with the protein data. UGT1A1 protein abundance was associated with multiple single nucleotide polymorphisms exhibiting noticeable ontogeny-genotype interplay. UGT2B15 rs1902023 (*2) was associated with decreased protein activity without any change in protein abundance. Taken together, these data are invaluable to facilitate the prediction of drug disposition in children using physiologically based pharmacokinetic modeling as demonstrated here for zidovudine and morphine.

Journal Title

Clinical pharmacology and therapeutics

Volume

105

Issue

1

First Page

131

Last Page

141

MeSH Keywords

Adolescent; Age Factors; Analgesics, Opioid; Antimetabolites; Child; Child, Preschool; Enzyme Activation; Genotype; Glucuronosyltransferase; Humans; Infant; Infant, Newborn; Microsomes, Liver; Morphine; Young Adult; Zidovudine

PubMed ID

29737521

Keywords

Age Factors; Opioid Analgesics; Antimetabolites; Enzyme Activation; Genotype; Glucuronosyltransferase; Microsomes, Liver; Morphine; Zidovudine

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