RT Journal Article SR Electronic T1 Biotransformation of the Chemopreventive Agent 2′,4′,4-Trihydroxychalcone (Isoliquiritigenin) by UDP-Glucuronosyltransferases JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 2104 OP 2112 DO 10.1124/dmd.108.021857 VO 36 IS 10 A1 Jian Guo A1 Ang Liu A1 Hongmei Cao A1 Yan Luo A1 John M. Pezzuto A1 Richard B. van Breemen YR 2008 UL http://dmd.aspetjournals.org/content/36/10/2104.abstract AB 2′,4′,4-Trihydroxychalcone (isoliquiritigenin), a chalcone found in licorice root and shallots, exhibits antioxidant, estrogenic, and antitumor activities. To complement our previous studies concerning the phase 1 metabolism of isoliquiritigenin, the phase 2 transformation of isoliquiritigenin by human hepatocytes and pooled human liver microsomes (HLMs) was investigated using liquid chromatography/tandem mass spectrometry and UV absorbance. Five glucuronides were detected corresponding to monoglucuronides of isoliquiritigenin and liquiritigenin, but no sulfate conjugates were observed. The UDP-glucuronosyltransferases (UGTs) involved in the formation of the major glucuronide conjugates were identified using recombinant human UGTs in combination with liquid chromatography/mass spectrometry. UGT1A1 and UGT1A9 were the major enzymes responsible for the formation of the most abundant conjugate, isoliquiritigenin 4′-O-glucuronide (MG5), with Km values of 4.30 ± 0.47 and 3.15 ± 0.24 μM, respectively. UGT1A1 and UGT1A10 converted isoliquiritigenin to the next most abundant phase 2 metabolite, isoliquiritigenin 2′-O-glucuronide (MG4), with Km values of 2.98 ± 0.8 and 25.8 ± 1.3 μM, respectively. In addition, isoliquiritigenin glucuronides MG4 and MG5 were formed by pooled human intestine and kidney microsomes, respectively. Based on the in vitro determination of a 25.3-min half-life for isoliquiritigenin when incubated with HLMs, the intrinsic clearance of isoliquiritigenin was estimated to be 36.4 ml/min/kg. These studies indicate that isoliquiritigenin will be conjugated rapidly in the liver to form up to five monoglucuronides. The American Society for Pharmacology and Experimental Therapeutics