Variability in PXR-mediated induction of CYP3A4 by commercial preparations and dry extracts of St. John's wort.
St. John's wort (SJW, Hypericum perforatum) is a well-tolerated herbal medicine widely used for the treatment of mild and moderate depressions. In the last 5 years, SJW has been implicated in drug interactions, which are largely mediated by the induction of the drug metabolizing enzymes, especially CYP3A4. There is still some controversy regarding the exact mechanism of induction and the identity of the SJW constituents involved. We investigated in LS174T cells the induction of CYP3A4 by ten SJW extracts, six commercial preparations, and the purified SJW constituent hyperforin. The content of hyperforin among the commercial preparations of SJW varied 62-fold (range 0.49-30.57 mg/dose). The CYP3A4 induction was mediated by PXR, but not by CAR. The magnitude of the induction correlated statistically significantly with the content of hyperforin in commercial SJW preparations (R = 0.87, p = 0.004) and in dry extracts (R = 0.65, p = 0.03), but not with their content of flavonoids or hypericin. Most of the CYP3A4 induction response occurred in the hyperforin range encountered in the blood of patients treated with SJW preparations. A temperature-induced decrease in the hyperforin content of a selected dry SJW extract abolished the induction of CYP3A4. In conclusion, commercial SJW preparations still exhibit an enormous variability in CYP3A4 induction, which is mediated by hyperforin and PXR. SJW preparations with lower hyperforin content should reduce the frequency of clinical interactions involving this herbal drug.
Gödtel-Armbrust
Ute
U
Institut für Pharmakologie, Johannes Gutenberg Universität, Obere Zahlbacher Str. 67, 55131 Mainz, Germany.
Metzger
Annegret
A
Kroll
Ulrike
U
Kelber
Olaf
O
Wojnowski
Leszek
L
D000873:Anthracenes; D001643:Bridged Bicyclo Compounds / Q000032:analysis; D002851:Chromatography, High Pressure Liquid; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000032:analysis; D006801:Humans; D020902:Hypericum; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology; D010696:Phloroglucinol / Q000031:analogs & derivatives / Q000032:analysis; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*; D020218:Response Elements; D013607:Tablets; D013729:Terpenes / Q000032:analysis; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
D000873:Anthracenes; D001643:Bridged Bicyclo Compounds; D000090702:Constitutive Androstane Receptor; D005419:Flavonoids; D010936:Plant Extracts; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013607:Tablets; D013729:Terpenes; D014157:Transcription Factors; D010569:Perylene; C004965:hypericin; D003577:Cytochrome P-450 Enzyme System; D010696:Phloroglucinol; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C001654:hyperforin