St John's wort, a herbal antidepressant, activates the steroid X receptor.
St John's wort (SJW), an extract of the medicinal plant Hypericum perforatum, is widely used as a herbal antidepressant. Recently, this agent has been found to adversely affect the metabolism of various coadministered drugs. Steroid X receptor (SXR), an orphan nuclear receptor, induces hepatic cytochrome P450 gene expression in response to diverse endogenous steroids, xenobiotics and drugs. Here, we report that, when coexpressed with SXR, a reporter construct derived from the cytochrome P450 3A promoter is activated by St John's wort. A GAL4-SXR ligand binding domain (LBD) fusion mediates concentration-dependent transactivation by SJW, whereas a mutant GAL4-SXR fusion, containing substitutions in key residues in a transactivation domain, is inactive. SJW recruits steroid receptor coactivator-1 to SXR in a two-hybrid assay and competes with radiolabelled ligand in binding studies, suggesting it interacts directly with the receptor LBD. Of two constituents of SJW, we find that hyperforin, but not hypericin, mediates both transactivation and coactivator recruitment by SXR. Our observations suggest that SXR activation by St John's wort mediates its adverse interaction with drugs metabolised via the CYP 3A pathway. Future development of SJW derivatives lacking SXR activation, may enable its antidepressant and drug-metabolising properties to be dissociated.
Wentworth
J M
JM
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.
Agostini
M
M
Love
J
J
Schwabe
J W
JW
Chatterjee
V K
VK
D000818:Animals; D000873:Anthracenes; D000928:Antidepressive Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds; D003345:Corticosterone / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051548:Histone Acetyltransferases; D006801:Humans; D020902:Hypericum; D051379:Mice; D056920:Nuclear Receptor Coactivator 1; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010569:Perylene / Q000031:analogs & derivatives / Q000494:pharmacology; D010696:Phloroglucinol / Q000031:analogs & derivatives; D010946:Plants, Medicinal; D000077297:Pregnane X Receptor; D011485:Protein Binding; D011987:Receptors, Steroid / Q000235:genetics*; D012293:Rifampin / Q000494:pharmacology; D013729:Terpenes / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D000873:Anthracenes; D000928:Antidepressive Agents; D001643:Bridged Bicyclo Compounds; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D013729:Terpenes; D014157:Transcription Factors; D010569:Perylene; C004965:hypericin; D003577:Cytochrome P-450 Enzyme System; D010696:Phloroglucinol; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1; C001654:hyperforin; D012293:Rifampin; D003345:Corticosterone