title: The Human UDP-glucuronosyltransferase UGT2A1 and UGT2A2 enzymes are highly active in bile acid glucuronidation.
abstract: Bile acids (BA) are essential modulators of lipid, glucose, and cholesterol homeostasis, but they exert cytotoxic effects in the cholestatic liver. Glucuronidation, catalyzed by the UDP-glucuronosyltransferase (UGT) enzymes is a pharmacologically relevant BA detoxification process. The present study characterized the BA-conjugating activity of the little-studied human UGTs of subfamily 2A: UGT2A1, 2A2, and 2A3. Recombinant UGT2As, expressed in baculovirus-infected insect cells, were assayed for the glucuronidation of six major bile acids: chenodeoxycholic acid (CDCA), cholic acid (CA), lithocholic acid (LCA), deoxycholic acid (DCA), hyocholic acid (HCA) and hyodeoxycholic acid (HDCA). UGT2A3 exhibited detectable but very low activity with all the tested BA substrates. UGT2A1 was highly efficient in forming LCA-3 and LCA-24G, CDCA-24, DCA-24, HCA-24, and HDCA-24G, whereas UGT2A2 was the most active enzyme for CA-24G and CDCA-24G formation and also was able to generate HDCA-6G, HDCA-24G, LCA-24G, and HCA-24G. The Km values of UGT2A1 varied between 102.2 ± 14.3 µM and 2.4 ± 1.2 mM. With the exception of CA-24G, a low affinity substrate for UGT2A2, all the Km values for UGT2A2 were in the 100 to 400 µM range. We demonstrate the high reactivity of the human UGT2A1 and UGT2A2 for bile acid glucuronidation. The physiologic importance of these reactions to BA disposition remains, however, to be clarified in vivo.
authors.affiliation: Laboratory of Molecular Pharmacology, CHU-Québec Research Centre, Faculty of Pharmacy, Laval University, Québec City, Québec, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Perreault
authors.forename: Louis
authors.initials: L
authors.lastname: Gauthier-Landry
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Trottier
authors.forename: Mélanie
authors.initials: M
authors.lastname: Verreault
authors.forename: Patrick
authors.initials: P
authors.lastname: Caron
authors.forename: Moshe
authors.initials: M
authors.lastname: Finel
authors.forename: Olivier
authors.initials: O
authors.lastname: Barbier
mesh_terms: D001647:Bile Acids and Salts / Q000378:metabolism*; D002635:Chenodeoxycholic Acid / Q000378:metabolism; D019826:Cholic Acid / Q000378:metabolism; D002793:Cholic Acids / Q000378:metabolism; D003840:Deoxycholic Acid / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D008095:Lithocholic Acid / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D002793:Cholic Acids; D003840:Deoxycholic Acid; D002635:Chenodeoxycholic Acid; C004821:muricholic acid; D008095:Lithocholic Acid; C010471:hyodeoxycholic acid; D014453:Glucuronosyltransferase; C577641:UGT2A1 protein, human; D019826:Cholic Acid