St. John's wort has been used as a medicinal plant for centuries and it has been widely assumed that, as a herbal preparation, it is harmless. However, in 2000, a seminal paper in The Lancet showed that the herb lowers plasma concentrations of indinavir, a protease inhibitor that is used to treat patients with HIV. Now, Mathijssen and colleagues, reporting in the 21 August issue of the Journal of the National Cancer Institute, show that it also interacts with a drug that is used to treat cancer, mitigating its effects in a similar way.
St. John's wort is thought to alleviate mild to moderate depression and is used widely among cancer patients. However, it is now recognized that the herbal medicine induces drug detoxification pathways — the cytochrome P450 enzyme system and the P-glycoprotein drug transporter — and so interferes with the metabolism of classes of drugs that are substrates for these pathways.
Mathijssen et al. conducted a small randomized study of five cancer patients, treating them with irinotecan with or without St. John's wort. Irinotecan is, in part, eliminated by routes that are mediated by an isoform of P450, CYP3A4. The authors report that plasma levels of the active metabolite, SN-38, were decreased by 42% after cotreatment with St. John's wort and that myelosuppression was also greatly reduced — about 60% with irinotecan alone, but less than 8% with the combination. As irinotecan has a narrow therapeutic index, decreased plasma concentrations might be expected to lead to loss of antitumour activity.
The authors conclude that irinotecan and St. John's wort should not be given in combination. They hypothesize that these results are probably representative of other anticancer drugs that are at least partial substrates for CYP3A4, such as etoposide, tamoxifen and paclitaxel. The understanding of drug metabolism and mechanism of action of herbal preparations, and their interactions, are therefore highlighted as key areas of cancer research.
ORIGINAL RESEARCH PAPER
Mathijssen, R. H. J. et al. Effects of St. John's Wort on irinotecan metabolism. J. Natl Cancer Inst. 94, 1247–1249 (2002)
Mansky, P. J. & Straus, S. E. St. John's Wort: more implications for cancer patients. J. Natl Cancer Inst. 94, 1187–1188 (2002)
Wang, Z. et al. The effects of St. John's wort (Hypericum perforatum) on human cytochrome P450 activity. Clin. Pharmacol. Ther. 70, 317–326 (2000)
About this article
Cite this article
Hutchinson, E. Not so innocent. Nat Rev Cancer 2, 720 (2002). https://doi.org/10.1038/nrc912