Differential UGT1A1 Induction by Chrysin in Primary Human Hepatocytes and HepG2 Cells

Chrysin, a dietary flavonoid, has been shown to markedly induce UGT1A1 expression and activity in HepG2 and Caco-2 cell lines; thus, it has been suggested to have clinical utility in the treatment of UGT1A1-mediated deficiencies, such as unconjugated hyperbilirubinemia or the prevention of 7-ethyl-1...

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Published in:	The Journal of pharmacology and experimental therapeutics 2005-12, Vol.315 (3), p.1256-1264
Main Authors:	Smith, Cornelia M, Graham, Richard A, Krol, Wojciech L, Silver, Ivin S, Negishi, Masahiko, Wang, Hongbing, Lecluyse, Edward L
Format:	Article
Language:	eng
Subjects:	Adolescent Adult African Continental Ancestry Group - genetics Aged Carcinogens - pharmacology Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - pathology Cell Line, Tumor Cells, Cultured Child, Preschool Dose-Response Relationship, Drug Drug Interactions Enzyme Induction - drug effects European Continental Ancestry Group - genetics Female Flavonoids - pharmacokinetics Flavonoids - pharmacology Genes, Reporter Glucuronosyltransferase - biosynthesis Glucuronosyltransferase - genetics Hepatocytes - drug effects Hepatocytes - enzymology Humans Liver Neoplasms - metabolism Liver Neoplasms - pathology Luciferases - metabolism Male Methylcholanthrene - pharmacology Middle Aged RNA, Messenger - analysis
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Summary:	Chrysin, a dietary flavonoid, has been shown to markedly induce UGT1A1 expression and activity in HepG2 and Caco-2 cell lines; thus, it has been suggested to have clinical utility in the treatment of UGT1A1-mediated deficiencies, such as unconjugated hyperbilirubinemia or the prevention of 7-ethyl-10-hydroxycamptothecin (SN-38) toxicity. However, little is known about its induction potential in a more physiologically relevant model system, such as primary hepatocyte culture. In this study, induction of UGT1A1 expression (mRNA, protein, and activity) was investigated in primary human hepatocyte cultures after treatment with chrysin and other prototypical inducers. Endogenous nuclear receptor-mediated UGT1A1 induction was studied using transient transfection reporter assays in primary human hepatocytes and HepG2 cells. Results indicated that induction of UGT1A1 expression was minimal in human hepatocytes treated with chrysin compared with that in HepG2 cells (1.2-versus 11-fold, respectively). Subsequent experiments to determine whether the differential response was due to its metabolic stability revealed strikingly different elimination rate constants between the two cell systems (half-life of 13 min in human hepatocytes versus 122 min in HepG2 cell suspensions). Further study demonstrated that UGT1A1 mRNA expression could be induced in human hepatocyte cultures by either increasing the chrysin dosing frequency or by modulating chrysin metabolism, suggesting that the differential induction observed in hepatocytes and HepG2 cells was due to differences in the metabolic clearance of chrysin. In conclusion, this study suggests that the metabolic stability of chrysin likely would limit its ability to induce UGT1A1 in vivo.
ISSN:	0022-3565 1521-0103