Medical College of Wisconsin
CTSIResearch InformaticsREDCap

Age- and Genotype-Dependent Variability in the Protein Abundance and Activity of Six Major Uridine Diphosphate-Glucuronosyltransferases in Human Liver. Clin Pharmacol Ther 2019 Jan;105(1):131-141

Date

05/09/2018

Pubmed ID

29737521

Pubmed Central ID

PMC6222000

DOI

10.1002/cpt.1109

Scopus ID

2-s2.0-85050913587 (requires institutional sign-in at Scopus site)   100 Citations

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.

Author List

Bhatt DK, Mehrotra A, Gaedigk A, Chapa R, Basit A, Zhang H, Choudhari P, Boberg M, Pearce RE, Gaedigk R, Broeckel U, Leeder JS, Prasad B

Author

Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

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