Distribution of Uridine Diphosphate-Glucuronosyltransferase (UGT) Expression and Activity in Cynomolgus Monkey Tissues: Evidence for Differential Expression of Steroid-Conjugating UGT Enzymes in Steroid Target Tissues*

Abstract

Based on the similarity of pathways and enzymes involved in steroid metabolism, simians represent a relevant animal model to study steroid elimination by glucuronidation. In this study the tissue distribution of UDP-glucuronosyltransferase (UGT) transcripts, proteins, and enzymatic activities were examined in 24 different cynomolgus monkey tissues. RT-PCR and Western blot analysis on total RNA and microsomal proteins demonstrated the presence of UGT1A and UGT2B transcripts and proteins in a wide range of tissues including steroid target tissues. Glucuronidation activity on eugenol, 5alpha-androstane-3alpha,17beta-diol, androsterone, and 4-hydroxyestradiol was measured using tissue homogenates and radiolabeled [14C]UDP-glucuronic acid. All tissues contained conjugation activity on these substrates, but glucuronidation rates were significantly lower in steroid target tissues than in liver, kidney, or gut. However, the ratio of steroid glucuronidation vs. eugenol glucuronidation was higher in steroid target tissues, suggesting a differential expression of steroid-conjugating enzymes in these tissues. Taken together, these results clearly demonstrate the presence of steroid glucuronidation enzymes in extrahepatic steroid target tissues and support the hypothesis that steroid glucuronidation is an important intracrine pathway involved in termination of steroid signaling.