Functional induction and de-induction of P-glycoprotein by St. John's wort and its ingredients in a human colon adenocarcinoma cell line.
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.
Tian
Run
R
Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Koyabu
Noriko
N
Morimoto
Satoshi
S
Shoyama
Yukihiro
Y
Ohtani
Hisakazu
H
Sawada
Yasufumi
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000230:Adenocarcinoma; D000818:Animals; D000873:Anthracenes; D001692:Biological Transport; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D004077:Digoxin / Q000378:metabolism; D006801:Humans; D020902:Hypericum; D018374:LLC-PK1 Cells; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology; D013552:Swine; D013729:Terpenes / Q000494:pharmacology*; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000873:Anthracenes; D001643:Bridged Bicyclo Compounds; D010936:Plant Extracts; D013729:Terpenes; D010569:Perylene; D004077:Digoxin; C004965:hypericin; D010696:Phloroglucinol; C001654:hyperforin; D012293:Rifampin