St. John's Wort: more implications for cancer patients.

St. John’s wort (Hypericum perforatum L.) has been used as a medicinal plant in Europe and Asia for centuries. Although it is best known today for its use by patients with mild to moderately severe depression, St. John’s wort has also been used orally as a traditional treatment for excitability, neuralgia, fibrositis, sciatica, and anxiety and as a topical preparation for the treatment of wounds (1). Concerns over its use have been raised with the recognition that, whatever its beneficial health effects might be, St. John’s wort interacts powerfully with many important drugs, potentially mitigating their effects (1). That herbal medicines may have adverse pharmacologic properties has come as a surprise to those who assumed that natural products must be safe. Yet, for products (be they synthetic drugs or complex herbal mixtures) to convey beneficial physiologic effects, we understand that the biochemical constituents in them must also harbor the risk for adverse effects. For herbal medicines, many such direct reactions are well described, including hypersensitivity reactions, liver toxicity, and coagulopathy (2). Herbal medicine–drug interactions were described only more recently. In addition to St. John’s wort, a number of herbal remedies have been identified that affect synthetic drug metabolism and, potentially, drug efficacy. According to a recent systematic review (2), four of the seven top-selling herbal medicines in this country interfere with the metabolism or efficacy of approved synthetic drugs: Ginkgo biloba (ginkgo) may enhance or alter the effects of warfarin, thiazide diuretics, and trazodone. Panax ginseng (ginseng) interacts with alcohol, warfarin, and phenelzine. Allium sativum (garlic) changes the pharmacokinetics of paracetamol and warfarin and the effects of chlorpropamide. Piper methysticum (kava) alters or enhances the effects of levodopa and alprazolam. Among these herbal medicines, the reports regarding drug interactions with St. John’s wort have been the most impressive. St. John’s wort induces highly promiscuous drug detoxification pathways and thus interferes with metabolism of many classes of drugs. Repeated administration of St. John’s wort results in potent and selective induction of cytochrome P450 (CYP) 3A in the intestinal wall and in the liver (3,4), apparently because the major constituent of St. John’s wort, hyperforin, is a ligand for the pregnane X receptor, which regulates expression of the CYP3A4 monooxygenase (5). Another constituent of St. John’s wort, hypericin, induces P-glycoprotein (Pgp)/MDR-1 expression in the intestinal wall in vitro and in vivo (3,6) and enhances the drug efflux function of Pgp (7). Hypericin also causes catalytic inhibition of human DNA topoisomerase II in cell cultures (8). The effects of St. John’s wort on drug levels have been confirmed in the clinic. A seminal study demonstrated that St. John’s wort statistically significantly lowers plasma concentrations of the human immunodeficiency virus-1 (HIV-1) protease inhibitor indinavir in normal volunteers, likely the result of CYP3A induction (9). After exposure to St. John’s wort, patients with HIV had increased plasma clearance of the non-nucleoside reverse transcriptase inhibitor nevirapine (10). These botanical– drug interactions are very disconcerting because the plasma level reductions of antiretroviral agents could expose affected patients to an increased risk for the development of viral drug resistance and disease progression. Similarly, in transplant patients, cyclosporin A levels were lower in patients taking St. John’s wort, likely the result of both Pgp activation and cytochrome P450 induction (11), which were associated with acute graft rejection in several patients (12). A recent case report