Hepatic Abundance and Activity of Androgen- and Drug-Metabolizing Enzyme UGT2B17 Are Associated with Genotype, Age, and Sex.
Document Type
Article
Publication Date
6-2018
Identifier
DOI: 10.1124/dmd.118.080952; PMCID: PMC5938891
Abstract
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.
Journal Title
Drug metabolism and disposition: the biological fate of chemicals
Volume
46
Issue
6
First Page
888
Last Page
896
MeSH Keywords
Adolescent; Adult; 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
PubMed ID
29602798
Keywords
Androgens; DNA Copy Number Variations; Genotype; Glucuronosyltransferase; Inactivation, Metabolic; Liver; Liver Microsome; Minor Histocompatibility Antigens; Single Nucleotide Polymorphism; Testosterone
Recommended Citation
Bhatt DK, Basit A, Zhang H, et al. Hepatic Abundance and Activity of Androgen- and Drug-Metabolizing Enzyme UGT2B17 Are Associated with Genotype, Age, and Sex. Drug Metab Dispos. 2018;46(6):888-896. doi:10.1124/dmd.118.080952
COinS
