Hepatic Abundance and Activity of Androgen- and Drug-Metabolizing Enzyme UGT2B17 Are Associated with Genotype, Age, and Sex. Drug Metab Dispos 2018 Jun;46(6):888-896
Date
04/01/2018Pubmed ID
29602798Pubmed Central ID
PMC5938891DOI
10.1124/dmd.118.080952Scopus ID
2-s2.0-85046695069 (requires institutional sign-in at Scopus site) 36 CitationsAbstract
The major objective of this study was to investigate the association of genetic and nongenetic factors with variability in protein abundance and in vitro activity of the androgen-metabolizing enzyme UGT2B17 in human liver microsomes (n = 455). UGT2B17 abundance was quantified by liquid chromatography-tandem mass spectrometry proteomics, and enzyme activity was determined by using testosterone and dihydrotestosterone as in vitro probe substrates. Genotyping or gene resequencing and mRNA expression were also evaluated. Multivariate analysis was used to test the association of UGT2B17 copy number variation, single nucleotide polymorphisms (SNPs), age, and sex with its mRNA expression, abundance, and activity. UGT2B17 gene copy number and SNPs (rs7436962, rs9996186, rs28374627, and rs4860305) were associated with gene expression, protein levels, and androgen glucuronidation rates in a gene dose-dependent manner. UGT2B17 protein (mean ± S.D. picomoles per milligram of microsomal protein) is sparsely expressed in children younger than 9 years (0.12 ± 0.24 years) but profoundly increases from age 9 years to adults (∼10-fold) with ∼2.6-fold greater abundance in males than in females (1.2 vs. 0.47). Association of androgen glucuronidation with UGT2B15 abundance was observed only in the low UGT2B17 expressers. These data can be used to predict variability in the metabolism of UGT2B17 substrates. Drug companies should include UGT2B17 in early phenotyping assays during drug discovery to avoid late clinical failures.
Author List
Bhatt DK, Basit A, Zhang H, Gaedigk A, Lee SB, Claw KG, Mehrotra A, Chaudhry AS, Pearce RE, Gaedigk R, Broeckel U, Thornton TA, Nickerson DA, Schuetz EG, Amory JK, Leeder JS, Prasad BAuthor
Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdolescentAdult
Aged
Aged, 80 and over
Androgens
Child
Child, Preschool
DNA Copy Number Variations
Female
Genotype
Glucuronosyltransferase
Humans
Inactivation, Metabolic
Infant
Infant, Newborn
Liver
Male
Microsomes, Liver
Middle Aged
Minor Histocompatibility Antigens
Polymorphism, Single Nucleotide
Testosterone
Young Adult
