Hypericum perforatum: which constituents may induce intestinal MDR1 and CYP3A4 mRNA expression?
In vitro and in vivo studies suggest that extracts of St John's wort (Hypericum perforatum, L .; SJWE) interact with various drugs, by enhancing their elimination, due to induction of intestinal and hepatic cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), the gene product of multidrug resistance gene 1 (MDR1/ABCB1). The aim of our study was to identify the major constituents responsible for this induction and their relative importance. Therefore, plant extracts were investigated that vary in these constituents with respect to their effect on mRNA expression of MDR1/CYP3A4. First, different pure constituents of Hypericum perforatum L . were investigated. Secondly, diverse SJWE with different concentrations of hyperforin, quercitrin and hypericin were investigated. The concentrations of hyperforin, hypericin, and quercitrin in the plant extracts were determined by HPLC, and an "artificial extract" containing the same mixture of these constituents was investigated. Different plant extracts, pure constituents or "artificial extracts" were applied to the human colon carcinoma-derived cell line (LS180) and the induction of MDR1 and CYP3A4 expression was analyzed by quantitative RT-PCR. MDR1 and CYP3A4 mRNA expression were both induced by single constituents of SJW such as hypericin and hyperforin in a concentration of 10 microM. Additionally, CYP3A4 mRNA expression was induced by quercitrin. SJW extracts containing hyperforin induced significantly MDR1 mRNA expression, whereas no CYP3A4 induction was observed after treatment with any of the investigated SJWE. These effects could be mimicked by "artificial extracts" containing the same compositions of hyperforin, hypericin and quercitrin as the plant extracts.
Gutmann
Heike
H
Department of Clinical Pharmacology & Toxicology, University Clinic Basel, Basel, Switzerland.
Poller
Birk
B
Büter
Karin Berger
KB
Pfrunder
Arabelle
A
Schaffner
Willi
W
Drewe
Jürgen
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D041743:Herb-Drug Interactions; D006801:Humans; D020902:Hypericum; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000928:Antidepressive Agents; D010936:Plant Extracts; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human