St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor.
St. John's wort (Hypericum perforatum) is an herbal remedy used widely for the treatment of depression. Recent clinical studies demonstrate that hypericum extracts increase the metabolism of various drugs, including combined oral contraceptives, cyclosporin, and indinavir. In this report, we show that hyperforin, a constituent of St. John's wort with antidepressant activity, is a potent ligand (K(i) = 27 nM) for the pregnane X receptor, an orphan nuclear receptor that regulates expression of the cytochrome P450 (CYP) 3A4 monooxygenase. Treatment of primary human hepatocytes with hypericum extracts or hyperforin results in a marked induction of CYP3A4 expression. Because CYP3A4 is involved in the oxidative metabolism of >50% of all drugs, our findings provide a molecular mechanism for the interaction of St. John's wort with drugs and suggest that hypericum extracts are likely to interact with many more drugs than previously had been realized.
Moore
L B
LB
Department of Molecular Endocrinology, Glaxo Wellcome Research and Development, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
Goodwin
B
B
Jones
S A
SA
Wisely
G B
GB
Serabjit-Singh
C J
CJ
Willson
T M
TM
Collins
J L
JL
Kliewer
S A
SA
D001643:Bridged Bicyclo Compounds; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D020902:Hypericum / Q000378:metabolism*; D008024:Ligands; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010696:Phloroglucinol / Q000031:analogs & derivatives; D010946:Plants, Medicinal; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists* / Q000378:metabolism; D013729:Terpenes / Q000378:metabolism / Q000494:pharmacology
D001643:Bridged Bicyclo Compounds; D008024:Ligands; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013729:Terpenes; D003577:Cytochrome P-450 Enzyme System; D010696:Phloroglucinol; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C001654:hyperforin