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 hyper icum extracts increase the metabolism of various drugs, including combined oral contraceptives, cyclosporin, and indinavir. In this report, we show th at hyperforin, a constituent of St. John's wort with antidepressant activit y, 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 extra cts or hyperforin results in a marked induction of CYP3A4 expression. Becau se 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 w ort with drugs and suggest that hypericum extracts are likely to interact w ith many more drugs than previously had been realized.