St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor

Abstract

St. John's wort (Hypericum perforatum) is an herbal remedy used widely for the treatment of depression. Recent clinical studies demonstrate that hypericum extracts increase the metabolism of various drugs, including combined oral contraceptives, cyclosporin, and indinavir. In this report, we show that hyperforin, a constituent of St. John's wort with antidepressant activity, is a potent ligand (Ki ‫؍‬ 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 extracts or hyperforin results in a marked induction of CYP3A4 expression. Because 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 wort with drugs and suggest that hypericum extracts are likely to interact with many more drugs than previously had been realized.

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

“…Although it appears paradoxical because the potential for drug-drug interactions and adverse drug reactions may increase [153], therapeutic targeting of CAR and PXR might be beneficial under certain conditions. Inhibition of CAR either by genetic ablation or by using CAR inverse agonists decreases acetaminopheninduced hepatotoxicity [154].…”

Pharmacokinetics and Drug Interactions of Herbal Medicines: A Missing Critical Step in the Phytomedicine/Drug Development Process

“…Hyperforin one of the constituents of St John's wort, purpoted to be the active constituent and the most potent agonist of PXR, has a Ki of 27nM (98).…”

“…For example, some models will maintain the structure and integrity of isolates and cellular cultures with a loss in quality and quantity of the target enzymes. Thus they may be useful for the study of Phase I and II reactions (106,107) but not suitable for inhibition and transport studies (108) due to the rapid down regulation of certain enzymes and transporters which occurs after isolation of hepatocytes. Primary liver cell cultures have been used for a long time to study inductive potentials of products but its major set back is the availability, quality and inter-individual variation of human liver tissue and the fact that it can only give information about the inductive capacity and not about the nuclear receptor involved.…”

“…The inductive capacity of SJW is mediated via this mechanism. Hyperforin, a bioactive constituent in St John's wort, forms a complex with the ligand-binding domain of human PXR thereby activating the PXR and consequently inducing CYP3A4 and CYP2C9 expression (86,87). Studies using gene reporter assays or measuring mRNA levels of CYP3A4 in human hepatocytes have also shown that gugulipid, or its chemical constituents guggulsterones, derived from the Mukul myrrh tree, hops, two traditional Chinese medicines (TCMs), Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch), and their selective constituents, carotenoids, especiallycarotene, and retinol have the potential to induce CYP3A4 by activation of PXR (88-90).…”

Essentials of Herb-Drug Interactions in the Elderly With Cardiovascular Disease

“…Its active constituent hyperforin is a well-known activator of the pregnane X receptor, 128 which results in enhanced expression of the drug efflux transporter ABCB1 (P-glycoprotein) 129 and induction of CYP3A4 (Table 3), an enzyme involved in metabolism of the majority of prescription medications used in cardiovascular practice. 130 Thus, potentially serious adverse reactions can occur from coadministration with drugs metabolized through CYP3A4 or transported by P-glycoprotein.…”