Document Detail

Induction of UDP-glucuronosyltransferase UGT1A1 by the flavonoid chrysin in the human hepatoma cell line hep G2.
MedLine Citation:
PMID:  10950852     Owner:  NLM     Status:  MEDLINE    
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 microM 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 (K(m) 0.35 microM). 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.
T Walle; Y Otake; A Galijatovic; J K Ritter; U K Walle
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  28     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2000 Sep 
Date Detail:
Created Date:  2000-10-04     Completed Date:  2000-10-04     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1077-82     Citation Subset:  IM    
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston 29425, USA.
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MeSH Terms
Bilirubin / metabolism
Blotting, Northern
Blotting, Western
Flavonoids / pharmacokinetics,  pharmacology*
Glucuronides / metabolism
Glucuronosyltransferase / drug effects*,  genetics,  metabolism
Microsomes, Liver / metabolism
RNA, Messenger / drug effects,  genetics,  metabolism
Tumor Cells, Cultured / drug effects,  enzymology,  metabolism
Reg. No./Substance:
0/Flavonoids; 0/Glucuronides; 0/RNA, Messenger; 480-40-0/chrysin; 635-65-4/Bilirubin; EC

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