Received for publication June 15, 2005.
Revised August 26, 2005.
Accepted for publication August 30, 2005.

DIFFERENTIAL UGT1A1 INDUCTION BY CHRYSIN IN PRIMARY HUMAN HEPATOCYTES AND HEPG2 CELLS

Abstract

Chrysin, a dietary flavonoid, has been shown to induce markedly UGT1A1 expression and activity in HepG2 and Caco-2 cell lines and, thus, has been suggested to have clinical utility in the treatment of UGT1A1-mediated deficiencies, such as unconjugated hyperbilirubinemia or the prevention of 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, 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 to that in HepG2 cells (1.2-fold vs. 11-fold, respectively). Subsequent experiments to determine if 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 vs. 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 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.

Key words: Chrysin, HepG2, Human hepatocytes, Induction, Metabolism, UGT1A1