RT Journal Article
SR Electronic
T1 Induction of UDP-Glucuronosyltransferase UGT1A1 by the Flavonoid Chrysin in the Human Hepatoma Cell Line Hep G2
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1077
OP 1082
VO 28
IS 9
A1 Thomas Walle
A1 Yoko Otake
A1 Alema Galijatovic
A1 Joseph K. Ritter
A1 U. Kristina Walle
YR 2000
UL http://dmd.aspetjournals.org/content/28/9/1077.abstract
AB The UDP-glucuronosyltransferases (UGTs) have long been known to be inducible by various chemicals, including drugs, although the extent of induction in general has been modest. In the present study, we determined the ability of the dietary flavonoid chrysin to induce UGT activity, protein and mRNA. When pretreating human hepatoma Hep G2 cells with 25 μM chrysin, the glucuronidation of chrysin itself increased 4.2-fold when measured in the intact cell and 14-fold in the cell homogenate, i.e., autoinduction. Microsomes from chrysin-treated cells probed with specific antibodies in Western analyses showed marked induction of the UGT1A family of proteins. Isoform-specific induction of the important hepatic UGT1A1 protein was observed but not of UGT1A6 or UGT2B7. The strong induction of UGT1A1 was confirmed by Northern analyses of total RNA as well as mRNA, using a specific probe. UGT1A1 message as well as protein was detectable also in untreated Hep G2 cells. In catalytic activity assays with recombinant UGT1A1, 1A4, 1A6 and 1A9, chrysin was found to be a high affinity substrate for UGT1A1 (Km 0.35 μM). Catalytic activity was also found for UGT1A9 and 1A6 but not for 1A4. Further studies demonstrated a 20-fold induction of the glucuronidation of bilirubin by the chrysin-treated cells and a 7.9-fold induction of the glucuronidation of the oral contraceptive drug ethinylestradiol, two of the best known and specific UGT1A1 substrates, demonstrating the potential importance of this induction. In view of these findings, it will be important to extend these studies to other dietary flavonoids. The American Society for Pharmacology and Experimental Therapeutics