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Drug Metab Dispos. 2018 Jun;46(6):888-896. doi: 10.1124/dmd.118.080952. Epub 2018 Mar 30.

Hepatic Abundance and Activity of Androgen- and Drug-Metabolizing Enzyme UGT2B17 Are Associated with Genotype, Age, and Sex.

Author information

1
Departments of Pharmaceutics (D.K.B., A.B., H.Z., K.G.C., A.M., B.P.), Genome Sciences (S.L., D.A.N.), Biostatistics (T.A.T.), and Medicine (J.K.A.), University of Washington, Seattle, Washington; Division of Pediatric Pharmacology and Medical Toxicology, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (A.G., R.E.P., R.G., J.S.L.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); and Section of Genomic Pediatrics, Department of Pediatrics, and Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin (U.B.).
2
Departments of Pharmaceutics (D.K.B., A.B., H.Z., K.G.C., A.M., B.P.), Genome Sciences (S.L., D.A.N.), Biostatistics (T.A.T.), and Medicine (J.K.A.), University of Washington, Seattle, Washington; Division of Pediatric Pharmacology and Medical Toxicology, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (A.G., R.E.P., R.G., J.S.L.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); and Section of Genomic Pediatrics, Department of Pediatrics, and Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin (U.B.) bhagwat@uw.edu.

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.

PMID:
29602798
PMCID:
PMC5938891
[Available on 2019-06-01]
DOI:
10.1124/dmd.118.080952
[Indexed for MEDLINE]

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