Absorption of kaempferol from endive, a source of kaempferol-3-glucuronide, in humans

OBJECTIVE: To determine the absorption, excretion and metabolism of kaempferol in humans. DESIGN: A pharmacokinetic study of kaempferol from endive over 24 h. SUBJECTS: Four healthy males and four healthy females. RESULTS: Kaempferol, from a relatively low dose (9 mg), was absorbed from endive with a mean maximum plasma concentration of 0.1 microM, at a time of 5.8 h, indicating absorption from the distal section of the small intestine and/or the colon. Although a 7.5-fold interindividual variation between the highest and lowest maximum plasma concentration was observed, most individuals showed remarkably consistent pharmacokinetic profiles. This contrasts with profiles for other flavonoids that are absorbed predominantly from the large intestine (eg rutin). An average of 1.9% of the kaempferol dose was excreted in 24 h. Most subjects also showed an early absorption peak, probably corresponding to kaempferol-3-glucoside, present at a level of 14% in the endive. Kaempferol-3-glucuronide was the major compound detected in plasma and urine. Quercetin was not detected in plasma or urine indicating a lack of phase I hydroxylation of kaempferol. CONCLUSIONS: Kaempferol is absorbed more efficiently than quercetin in humans even at low oral doses. The predominant form in plasma is a 3-glucuronide conjugate, and interindividual variation in absorption and excretion is low, suggesting that urinary kaempferol could be used as a biomarker for exposure.     

Expression and possible function of IL-2 and IL-15 receptors on human uveal melanoma cells

PURPOSE: Interleukin-2 (IL-2) and IL-15 receptors have been detected on some murine neoplasms. Accordingly, the expression of these receptors on human uveal melanoma cell lines was examined, and the effect of exogenous IL-2 and -15 on melanoma cell proliferation, susceptibility to natural killer (NK) cell-mediated cytolysis, and sensitivity to apoptosis were assessed. METHODS: Nine human uveal melanoma cell lines and three cell lines from uveal melanoma metastases were tested by flow cytometry for the expression of human IL-2R and -15Ralpha. Melanoma cells were cultured, with or without recombinant human IL-2 or -15, cell proliferation was determined by tritiated thymidine incorporation, and IL-2 and -15 receptor expression was assessed by flow cytometry. The effect of these cytokines on NK activity was evaluated with a standard (51)Cr-release assay. RESULTS: All the melanoma cell lines expressed IL-2R and -15R. IL-2 induced a three- to eightfold upregulation of IL-2R expression in all the melanoma cell lines. Although IL-2 did not affect the proliferation of six of the seven uveal melanoma cell lines, it induced a 32% and 57% increase in the proliferation of both metastatic cell lines. IL-15 induced proliferation on all tested cell lines (4%-68%). Both IL-2 and -15 reduced melanoma cell sensitivity to NK-cell-mediated cytolysis and cisplatin-induced apoptosis. CONCLUSIONS: The results suggest that IL-2 and -15 elaborated by tumor-infiltrating lymphocytes and macrophages may affect the malignant behavior of human uveal melanoma by stimulating proliferation and reducing uveal melanoma cell susceptibility to NK-cell-mediated cytolysis and cisplatin-induced apoptosis.     

Estrogenic activity of herbs commonly used as remedies for menopausal symptoms

OBJECTIVE: Women are increasingly turning to herbal therapies in an effort to manage their menopausal symptoms. In this study, we investigate the estrogenic activity of four selected herbs commonly used in menopause, namely dong quai, ginseng, black cohosh, and licorice root. DESIGN: We investigated the effect of these selected herbs on cell proliferation of MCF-7 cells, a human breast cancer cell line. We also assessed their estrogenic activity in a transient gene expression assay system using HeLa cells co-transfected with an estrogen-dependent reporter plasmid in the presence of human estrogen receptor ER alpha or ER beta cDNA. Finally, we investigated the estrogenic activity of these herbs using a bioassay in mice. RESULTS: Dong quai and ginseng both significantly induced the growth of MCF-7 cells by 16- and 27-fold, respectively, over that of untreated control cells, while black cohosh and licorice root did not. The herbs tested failed to show transactivation of either hER alpha or hER beta and had no effect on uterine weight in vivo when administered orally to mice for a period of 4 days. CONCLUSIONS: Our studies show that dong quai and ginseng stimulate the growth of MCF-7 cells independent of estrogenic activity. Because of the lack of efficacy and the potential for adverse effects, use of these herbs in humans warrants caution pending further study.     

Hydrolysis by lactase phlorizin hydrolase is the first step in the uptake of daidzein glucosides by rat small intestine in vitro

1. Isoflavones are naturally occurring oestrogenic compounds found in plants, where they exist in the glycosylated form. A proportion of ingested glycosides appears to be absorbed in the upper gastrointestinal tract, where enterocytes play an important role in their metabolism. 2. One hypothesis is that ingestion may involve hydrolysis by the luminally exposed enzyme lactase phlorizin hydrolase (LPH), an enzyme expressed specifically at the small intestinal brush border. 3. Using an everted sac preparation of rat jejunum and an inhibitor of LPH, we investigated the absorption of daidzein-O(7)-glucoside (daidzin) and the effect of LPH inhibition on this process. It was demonstrated that LPH plays a major role in the deglycosylation of daidzin. 4. The hydrolysis product, daidzein, is absorbed by epithelial cells and glucuronidated to daidzein-O(7)-glucuronide, which is subsequently exported primarily to the serosal (vascular) side of the tissue rather than to the luminal side. 5. A small but significant proportion of the intact glycoside is also transferred to the serosal compartment, and in the presence of an LPH inhibitor this was enhanced with a corresponding reduction in deglucosylation and glucuronidation. 6. The results indicate that that LPH plays an important role in the metabolism of glycosylated phytochemicals, and that the expression and activity of this enzyme in the small intestine can modify the profile of metabolites appearing in the circulation.     

Chemoprevention of prostate cancer by diet-derived antioxidant agents and hormonal manipulation (Review)

Cancer of the prostate is the most commonly diagnosed solid malignancy and the second leading cause of cancer-related death in men living in developed countries. With an ageing population, the number of men living with early stages of prostate cancer is expected to increase. There is an increasing need to prevent the onset of cancer or delay the progression of carcinogenesis in this organ. Chemoprevention is the administration of pharmacological agents to prevent, delay or reverse carcinogenesis. An example is the reversal of high grade intraepithelial neoplasia by hormonal manipulation using anti-oestrogens in breast carcinogenesis or anti-androgens in prostate carcinogenesis. Epidemiological data showing ethnic and geographic variations in the incidence of, and mortality from, prostate cancer have suggested that the consumption of certain dietary factors, particularly anti-oxidants, may be protective. These factors include the vitamins D and E, soy, lycopene and selenium. The administration of 5-alpha reductase inhibitors to patients with benign prostatic hyperplasia may also constitute a potentially chemopreventive intervention. The efficacy of chemopreventive agents needs to be investigated in randomised, placebo-controlled trials in suitable cohorts of high-risk individuals. In parallel, reliable assays of potential biomarkers of the efficacy of intervention need to be developed and validated rigorously.