Promiscuity and Quantitative Contribution of UGT2B17 in Drug and Steroid Metabolism Determined by Experimental and Computational Approaches.

ABSTRACT

Uridine 5'-diphospho-glulcuronosyltransferase 2B17 (UGT2B17) is important in the metabolism of steroids and orally administered drugs due to its high interindividual variability. However, the structural basis governing the substrate selectivity or inhibition of UGT2B17 remains poorly understood. This study investigated 76 FDA-approved drugs and 20 steroids known to undergo glucuronidation for their metabolism by UGT2B17. Specifically, we assessed the substrate selectivity for UGT2B17 over other UGT enzymes using recombinant human UGT2B17 (rUGT2B17), human intestinal microsomes, and human liver microsomes. The quantitative contribution of intestinal UGT2B17 in the glucuronidation of these compounds was characterized using intestinal microsomes isolated from UGT2B17 expressors and nonexpressors. In addition, a structure-based pharmacophore model for UGT2B17 substrates was built and validated using the studied pool of substrates and nonsubstrates. The results show that UGT2B17 could metabolize 23 out of 96 compounds from various chemical classes, including alcohols and carboxylic acids, particularly in the intestine. Interestingly, amines were less susceptible to UGT2B17 metabolism, though they could inhibit the enzyme. Three main pharmacophoric features of UGT2B17 substrates include (1) the presence of an accessible -OH or -COOH group near His35 residue, (2) a hydrophobic functional group at ∼4.5-5 Šfrom feature 1, and (3) an aromatic ring ∼5-7 Šfrom feature 2. Most of the studied compounds inhibited UGT2B17 activity irrespective of their substrate potential, indicating the possibility of multiple mechanisms. These data suggest that UGT2B17 is promiscuous in substrate selectivity and inhibition and has a high potential to produce significant variability in the absorption and disposition of orally administered drugs.