Identification of Human UDP-Glucuronosyltransferase Isoforms Responsible for the Glucuronidation of Glycyrrhetinic Acid

Abstract

  Glycyrrhetinic acid, the active metabolite of glycyrrhizin, is primarily eliminated by glucuronidation reaction in vivo. In spite of the widespread clinical use of glycyrrhizin, UDP-glucuronosyltransferase (UGT) isoforms involved in the glucuronidation of this drug are still unknown. This report identifies and characterizes the UGT isoforms responsible for glycyrrhetinic acid glucuronidation. In the enzymatic kinetic experiment performed with pooled human liver microsomes (HLMs), K_m was 39.4 μM and V_max was 609.2 pmol/min/mg protein. Of the baculosomes expressing 12 recombinant UGTs investigated, UGT1A1, 1A3, 2B4 and 2B7 showed catalytic activity and UGT1A3 exhibited the highest activity. K_m values of recombinant UGT1A3 and 2B7 were 3.4 and 4.4 μM, respectively. Both imipramine (typical substrate of UGT1A3 and 1A4) and flurbiprofen (typical substrate of UGT2B7) inhibit the glucuronidation of glycyrrhetinic acid. Estimated IC₅₀ values were 138 μM for flurbiprofen and 207 μM for imipramine in the inhibition of the glucuronidation of glycyrrhetinic acid in HLMs. These results suggest that glycyrrhetinic acid glucuronidation is primarily mediated by UGT1A1, 1A3, 2B4 and 2B7.