St John's wort, a herbal antidepressant, activates the steroid X receptor

St John's wort (SJW). an extract of the medicinal plant Hypericum perforatu m, 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 cytoc hrome P450 gene expression in response to diverse endogenous steroids, xeno biotics and drugs. Here, we report that, when coexpressed with SXR, a repor ter construct derived from the cytochrome P450 3A promoter is activated by St John's wort. A GAL4-SXR ligand binding domain (LBD) fusion mediates conc entration-dependent transactivation by SJW, whereas a mutant GAL4-SXR fusio n, containing substitutions: in key residues in a transactivation domain, i s inactive. SJW recruits steroid receptor coactivator-l to SXR in a two-hyb rid assay and competes with radiolabelled ligand in binding studies, sugges ting it interacts directly with the receptor LED. Of two constituents of SJ W, we find that hyperforin, but not hypericin, mediates both transactivatio n and coactivator recruitment by SXR. Our observations suggest that SXR act ivation by St John's wort mediates its adverse interaction with drugs metab olised via the CYP 3A pathway. Future development of SJW derivatives lackin g SXR activation, may enable its antidepressant and drug-metabolising prope rties to be dissociated.