Hepatic and Biliary Glucuronidation of Bisphenol A in Mice: A Reaction Catalyzed by the UDP-Glucuronosyltransferase (Ugt2b)1 and Ugt2b34 Enzymes

Bisphenol A (BPA) is an important industrial chemical used in the manufacture of polycarbonate plastic and epoxy resin-based products. This endocrine disruptor molecule is metabolized and eliminated primarily as a monoglucuronide. The purpose of this study was to identify those of murine tissues and UDP-glucuronosyltransferase (UGT) enzymes involved in BPA-glucuronide (-G) formation. A series of in vitro glucuronidation assays were performed using homogenates or microsomal fractions from murine tissues or HEK293 cells expressing each of the 7 murine Ugt2b isoforms. From the 29 tissues tested, the most reactive were the liver, gallbladder, caecum and colon. A low BPA-G formation was also detected in the ileum, oviduct and testis. KM values ranged from 19.6±7.5 (gallbladder) to 85.8±16.0µM (caecum), while with 190.3µL/min/mg proteins the gallbladder exhibited the highest intrinsic clearance value. From the 7 murine Ugt2bs, the highest BPA-G formation rates were obtained with the Ugt2b1 and Ugt2b34 isoforms. These 2 enzymes displayed important differences in terms of kinetic parameters: Ugt2b1 exhibited lower KM and Vmaxapp. values (2.5±0.2µM and 389.4±79.0pmol/min/mg proteins, respectively) than Ug2b34 (KM=98.4±3.3µM and Vmaxapp.=9,681.3±1,507.3pmol/min/mg proteins). However, CLINT. values revealed that both enzymes exhibit similar BPA glucuronidation efficiencies. Quantitative RT-PCR experiments further revealed that the profile of the Ugt2b34 mRNA expression correlates with BPA-G formation in tissues of the gastro-intestinal tract. In conclusion, the present study identifies tissues of the hepato-biliary-intestinal tract as well as the Ugt2b1 and Ugt2b34 isoforms as major contributors for bisphenol A glucuronidation in mice Surprisingly, gallbladder was very reactive with this substrate.