Vol. 30, Issue 5, 576-581, May 2002

Glucuronidation versus Oxidation of the Flavonoid Galangin by Human Liver Microsomes and Hepatocytes

Yoko Otake, Faye Hsieh, and Thomas Walle

Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina (Y.O., T.W.); and Amgen Inc., Thousands Oaks, California (F.H.)

In a previous study, we used human liver microsomes for the first time to study cytochrome P450 (P450)-mediated oxidation of the flavonoid galangin. The combination of CYP1A2 and CYP2C9 produced a V_max/K_m value of 13.6 ± 1.1 µl/min/mg of protein. In the present extended study, we determined glucuronidation rates for galangin with the same microsomes. Two major and one minor glucuronide were identified by liquid chromatography/mass spectrometry. The V_max/K_m values for the two major glucuronides conjugated in the 7- and 3-positions were 155 ± 30 and 427 ± 26 µl/min/mg of protein, thus, exceeding that of oxidation by 11 and 31 times, respectively. This highly efficient glucuronidation appeared to be catalyzed mainly by the UDP-glucuronosyltransferase (UGT)1A9 isoform but also by UGT1A1 and UGT2B15. Sulfation of galangin by the human liver cytosol, mediated mainly but not exclusively by sulfotransferase (SULT) 1A1, also appeared to be efficient. These conclusions were strongly supported by experiments using the S9 fraction of the human liver, in which all three metabolic pathways could be directly compared. When galangin metabolism was examined in fresh plated hepatocytes from six donors, glucuronidation clearly predominated followed by sulfation. Oxidation occurred only to a minor extent in two of the donors. This study for the first time establishes that glucuronidation and sulfation of galangin, and maybe other flavonoids, are more efficient than P450-mediated oxidation, clearly being the metabolic pathways of choice in intact cells and therefore likely also in vivo.