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Drug Metabolism and Disposition Fast Forward
First published on January 7, 2005; DOI: 10.1124/dmd.104.002485

0090-9556/05/3304-547-554$20.00
DMD 33:547-554, 2005

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FUNCTIONAL INDUCTION AND DE-INDUCTION OF P-GLYCOPROTEIN BY ST. JOHN'S WORT AND ITS INGREDIENTS IN A HUMAN COLON ADENOCARCINOMA CELL LINE

Run Tian, Noriko Koyabu, Satoshi Morimoto, Yukihiro Shoyama, Hisakazu Ohtani, and Yasufumi Sawada

Department of Medico-Pharmaceutical Sciences (R.T., N.K., H.O., Y.Sa.) and Department of Pharmacognosy (S.M., Y.Sh.), Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

Continuous use of St. John's wort decreases the bioavailabilities of a variety of drugs. This interaction is attributed to the induction of cytochrome P450 3A4 and/or P-glycoprotein. In this study, we aimed to examine the chronic effects of St. John's wort and its constituents, hyperforin and hypericin, on the expression and function of P-glycoprotein in an intestinal cell line, LS 180. We also examined the acute inhibitory effect of St. John's wort on P-glycoprotein by using LLC-GA5-COL150 cells, which overexpress P-glycoprotein. St. John's wort and hyperforin but not hypericin increased the expression of P-glycoprotein in LS 180 cells. Removal of St. John's wort resulted in a restoration of P-glycoprotein level within 48 h. The content of hyperforin in St. John's wort extract was high enough to induce P-glycoprotein, suggesting that the induction of P-glycoprotein by St. John's wort can be almost attributable to hyperforin. The LS 180 cells chronically exposed to St. John's wort or hyperforin exhibited the increase in the function of P-glycoprotein assessed by the efflux of digoxin, and the activities correlated well with P-glycoprotein level. On the other hand, St. John's wort and its two constituents did not show any acute effect on P-glycoprotein-mediated transport of digoxin. St. John's wort induced P-glycoprotein in vitro that functions as a drug efflux pump. Hyperforin is considered to be a primary cause of the inductive effect of St. John's wort. Long-term administration of St. John's wort may cause clinically significant decrease in the plasma concentrations of P-glycoprotein substrates.

Address correspondence to: Dr. Yasufumi Sawada, Professor, Department of Drug Informatics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: sawada{at}phar.kyushu-u.ac.jp




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