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Vol. 28, Issue 9, 1077-1082, September 2000
Department of Cell and Molecular Pharmacology and Experimental
Therapeutics, Medical University of South Carolina, Charleston, South
Carolina (T.W., Y.O., A.G., U.K.W.); and Department of Pharmacology
and Toxicology, Medical College of Virginia at Virginia Commonwealth
University, Richmond, Virginia (J.K.R.)
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.
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