TY - JOUR T1 - Hepatic Abundance and Activity of Androgen and Drug Metabolizing Enzyme, UGT2B17, are Associated with Genotype, Age, and Sex JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.118.080952 SP - dmd.118.080952 AU - Deepak Kumar Bhatt AU - Abdul Basit AU - Haeyoung Zhang AU - Andrea Gaedigk AU - Seung-been Lee AU - Katrina G Claw AU - Aanchal Mehrotra AU - Amarjit S Chaudhry AU - Robin E. Pearce AU - Roger Gaedigk AU - Ulrich Broeckel AU - Timothy A Thornton AU - Deborah A. Nickerson AU - Erin G. Schuetz AU - John Amory AU - J. Steven Leeder AU - Bhagwat Prasad Y1 - 2018/01/01 UR - http://dmd.aspetjournals.org/content/early/2018/03/30/dmd.118.080952.abstract N2 - The major objective of this study was to investigate association of genetic and non-genetic 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 LC-MS/MS 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 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 ± SD pmol per mg microsomal protein) is sparsely expressed in children below 9 years (0.12 ± 0.24), but profoundly increases from age 9 years to adults (~10 fold) with ~2.6-fold higher abundance in males than females (1.2 vs. 0.47). Association of androgen glucuronidation with UGT2B15 abundance was only observed 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. ER -