St. John's wort attenuates irinotecan-induced diarrhea via down-regulation of intestinal pro-inflammatory cytokines and inhibition of intestinal epithelial apoptosis

Department of Pharmacy, Faculty of Science, National University of Singapore, Science Drive 4, Singapore 117543, Singapore.
Toxicology and Applied Pharmacology (Impact Factor: 3.71). 11/2006; 216(2):225-37. DOI: 10.1016/j.taap.2006.05.020
Source: PubMed


Diarrhea is a common dose-limiting toxicity associated with cancer chemotherapy, in particular for drugs such as irinotecan (CPT-11), 5-fluouracil, oxaliplatin, capecitabine and raltitrexed. St. John's wort (Hypericum perforatum, SJW) has anti-inflammatory activity, and our preliminary study in the rat and a pilot study in cancer patients found that treatment of SJW alleviated irinotecan-induced diarrhea. In the present study, we investigated whether SJW modulated various pro-inflammatory cytokines including interleukins (IL-1beta, IL-2, IL-6), interferon (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) and intestinal epithelium apoptosis in rats. The rats were treated with irinotecan at 60 mg/kg for 4 days in combination with oral SJW or SJW-free control vehicle at 400 mg/kg for 8 days. Diarrhea, tissue damage, body weight loss, various cytokines including IL-1beta, IL-2, IL-6, IFN-gamma and TNF-alpha and intestinal epithelial apoptosis were monitored over 11 days. Our studies demonstrated that combined SJW markedly reduced CPT-11-induced diarrhea and intestinal lesions. The production of pro-inflammatory cytokines such as IL-1beta, IFN-gamma and TNF-alpha was significantly up-regulated in intestine. In the mean time, combined SJW significantly suppressed the intestinal epithelial apoptosis induced by CPT-11 over days 5-11. In particular, combination of SJW significantly inhibited the expression of TNF-alpha mRNA in the intestine over days 5-11. In conclusion, inhibition of pro-inflammatory cytokines and intestinal epithelium apoptosis partly explained the protective effect of SJW against the intestinal toxicities induced by irinotecan. Further studies are warranted to explore the potential for STW as an agent in combination with chemotherapeutic drugs to lower their dose-limiting toxicities.

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    • "SN-38 is then glucuronidated in the liver by uridine diphosphate (UDP)-glurunosyltransf erase to form SN-38G,69 which is secreted through the bile into the small intestine. As with other compounds, this inactive form is then reactivated by bacterial p-glucuronidases,70 contributing to the development of delayed-onset diarrhea in 40% of treated patients.71,72 "
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    • "There are few reports on the effect of SJW on gastrointestinal functions. Previous investigators have shown that extracts from Hypericum perforatum decreased gastric acid secretion in pylorus-ligated rats (Abdel-Salam 2005), reduced spontaneous contractions of the isolated rabbit jejunum (Gilani et al. 2005), inhibited irinotecaninduced diarrhea and intestinal damage in rats (Hu et al. 2006), and inhibited iNOS expression in human intestinal cell lines (Tedeschi et al. 2003). In the present study, we have shown that SJW extract delayed gastric emptying in a dose-dependent fashion. "
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    ABSTRACT: St. John's wort (Hypericum perforatum) is a highly popular and effective herbal antidepressant that clinically interacts with a number of conventional drugs. Because alterations in gastric emptying can cause pharmacokinetic interactions, in the present study we evaluated the effect of a standardized extract prepared from the flowering tops of Hypericum perforatum (SJW extract) on rat gastric motility. Orally administered SJW extract delayed gastric emptying in vivo. In vitro studies showed that SJW extract was significantly more active in inhibiting acetylcholine (or prostaglandin E2)-induced contractions than electrical field stimulation (EFS)-induced contractions. The effect of SJW extract on EFS-induced contractions was unaffected by drugs that inhibit intrinsic inhibitory nerves or by tachykinin antagonists, but it was reduced by the 5-hydroxytryptamine antagonist methysergide. The inhibitory effect of SJW extract on acetylcholine-induced contractions was reduced by the sarcoplasmic reticulum Ca2+-ATPase inhibitor cyclopiazonic acid, but not by the L-type Ca2+ channel blocker nifedipine or by methysergide. Among the chemical constituents of SJW extract tested, hyperforin and, to a lesser extent, the flavonoids kaempferol and quercitrin, inhibited acetylcholine-induced contractions. It is concluded that SJW has a direct inhibitory effect on smooth muscle and could also possibly modulate gastric neurotransmission. If extended to humans, the inhibitory effect of SJW extract on gastric emptying in vivo could contribute, at least in part, to the clinical pharmacokinetic interactions between conventional medicines and this herbal antidepressant.
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    • "The article by Hu et al. (2006) on St. John's wort and irinotecan-induced diarrhea ignores the well-known CYP450 and P-glycoprotein effects of St. John's wort on drug metabolism. It is also troubling that the authors appear to misrepresent the study by Mathijssen et al. (2002) when they state: " Interestingly, a recent pilot study in 5 cancer patients found that oral treatment of SJW at 900 mg/day for 18 days alleviated irinotecan-induced diarrhea (Mathijssen et al., 2002). "

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