RESUMEN
Epidemiological studies have demonstrated that dietary modifications can reduce the incidence of cancer. Specifically, diets high in vegetables and fruits are associated with lower rates of cancer at many sites. Somatic mutations have a critical role in carcinogenesis suggesting the use of in vivo mutation assays as an alternative approach to studying the relationship between diet and cancer. Since the rate of accumulation of spontaneous mutations is highest during growth and development early in life, we tested whether certain foods as dietary supplements could reduce the rate of mutation during this period using lacZ transgenic mice. Pregnant female mice were placed on a control diet or a diet supplemented to 20% final dry weight with broccoli, cabbage, carrots, flaxseed, green peas, green peppers, oranges or strawberries for the entire duration of their pregnancy and lactation. Mutation frequencies were subsequently measured at the lacZ transgene in colonic epithelial cells of the offspring at 3 weeks of age. A small number of measurements were also made on siblings at 8 weeks of age. While the control AIN-96G diet on its own resulted in lower mutant frequencies than had been observed in earlier experiments with lab chow, no significant reduction in mutant frequencies was detected for any of the foods tested as compared to the AIN-93G diet alone. Significantly more mutations were found at 3 weeks of age in mice fed diets supplemented with broccoli or oranges, but the result with oranges may be the result of jackpot mutations.
Asunto(s)
Colon/crecimiento & desarrollo , Suplementos Dietéticos , Operón Lac , Mutación , Animales , Femenino , Frecuencia de los Genes , Ratones , Ratones Transgénicos , EmbarazoRESUMEN
Spontaneous genetic damage, whether mutations or chromosomal aberrations, undoubtedly arise from a variety of sources including replication errors, oxidative damage, background radiation, and chemical exposure. Given the numerous correlations between diet and cancer, it seemed possible that diet could influence the spontaneous rate of DNA damage and its genetic consequences. Since diets high in vegetables, fruits, and grains are associated with lower rates of cancer, we supplemented the diets of mice and measured the frequency of micronuclei in the peripheral blood. Micronuclei arise from broken chromosomes or chromosome loss in the erythroblast. They are first seen in the short reticulocyte stage of the red blood cell but persist for the entire 30-day lifespan of the cell in mice. C57Bl mice were placed on a defined diet (AIN-93G) supplemented to 20% final dry weight with grains or freeze-dried fruits or vegetables. The micronucleus frequency was measured in a pre-exposure blood sample and every 2 weeks thereafter for 6 weeks. This was possible in spite of the low spontaneous frequency of 1/1000-2/1000 cells by the use of a novel flow cytometric method, which permitted the analysis of both the mature red blood cells and reticulocytes. Of the foods tested, flaxseed proved to be the most protective by reducing the incidence of micronuclei in both the reticulocyte and normochromatic erythrocyte cell populations by 30 and 11%, respectively. The results show that at least one class of spontaneous genetic damage can be modified by diet and suggests that short-term experiments with small numbers of animals can be used to identify dietary anticarcinogens that may influence human cancer rates.
Asunto(s)
Daño del ADN , Suplementos Dietéticos , Lino , Animales , Aberraciones Cromosómicas , Grano Comestible , Femenino , Frutas , Ratones , Ratones Endogámicos C57BL , Pruebas de Micronúcleos , Esplenectomía , VerdurasAsunto(s)
Anticarcinógenos/farmacología , Biomarcadores de Tumor/análisis , Neoplasias del Colon/prevención & control , Fibras de la Dieta/análisis , Ácido Fítico/farmacología , Animales , Apoptosis/efectos de los fármacos , Biomarcadores , División Celular/efectos de los fármacos , Neoplasias del Colon/inducido químicamente , Masculino , Lesiones Precancerosas/inducido químicamente , Lesiones Precancerosas/prevención & control , Ratas , Ratas Endogámicas F344 , Factores de RiesgoRESUMEN
Due to the potential oestrogenic effects of secoisolariciresinol diglycoside (SDG), the mammalian lignan precursor in flaxseed (Linum usitatissimum), we hypothesized that exposure to purified SDG during early life would have a positive effect on developing bone. This present study determined whether exposure to SDG purified from flaxseed during suckling via mother's milk or continuously to adolescence (postnatal day (PND) 50) or adulthood (PND 132) increased bone mineral content (BMC) or bone strength in female rat offspring. Offspring were exposed to basal diet (BD) or one of two doses of SDG (50S, 100S) equivalent to that in a 50 or 100 g flaxseed/kg diet during lactation only or through to PND 50 or 132. At PND 50 and 132, femurs were analysed for BMC by dual energy X-ray absorptiometry and biomechanical strength by a 3-point bending test. Compared with BD group, rats exposed to continuous 50S or 100S diet had stronger femurs at PND 50 without changes in BMC. At PND 132 there were no differences in femur strength despite the fact that continuous exposure to BD resulted in a higher BMC than rats exposed to 100S during lactation only or to 50S or 100S during lactation through to adulthood. In conclusion, female rat bone is more sensitive to the oestrogen-like action of lignans during early life when endogenous levels of sex hormones are low, but by adulthood the improved bone strength does not persist. Importantly, exposure to purified lignan does not have negative effects on bone strength.
Asunto(s)
Densidad Ósea/efectos de los fármacos , Desarrollo Óseo/efectos de los fármacos , Estrógenos/administración & dosificación , Lignanos/administración & dosificación , Absorciometría de Fotón , Animales , Animales Lactantes , Fenómenos Biomecánicos , Femenino , Fémur , Lino , Embarazo , Ratas , Ratas Sprague-DawleyRESUMEN
Flaxseed is the richest source of the plant lignan secoisolariciresinol diglycoside (SDG), which is converted to the two major mammalian lignans, enterodiol (ED) and enterolactone (EL), by colonic bacteria. Because both ED and EL can produce biological effects similar to estrogen, exposure to lignans during early stages of development may adversely alter the normal development of bone in males since bone is a hormone-sensitive tissue. To determine whether early exposure to flaxseed or its lignan compromised the acquisition of bone mass or reduced bone strength, male offspring were exposed to one of three diets during lactation only (birth through postnatal day [PND] 21) via mother's milk or continuously from the start of lactation through to adolescence (PND 50) or young adulthood (PND 132). The diets were a basal diet (BD) that was devoid of phytoestrogens, BD containing 10% flaxseed, or BD containing the equivalent quantity of SDG present in a 10% flaxseed diet. To assess bone quantity, the bone mineral content (BMC) and bone mineral density (BMD) of femurs were assessed by dual-energy x-ray absorptiometry. Since the biomechanical properties of bone are indicators of the microarchitecture and thus bone quality, the biomechanical strength of femurs was assessed by three-point bending. At PND 50, ultimate bending stress and Young's modulus, measures of bone strength, were reduced among rats that received the 10% flaxseed diet from PND 0 through PND 50, while there were no marked differences in bone size, BMC, or BMD among groups. Interestingly, this effect does not appear to be due to the lignan in flaxseed, as continuous exposure to the diet containing the equivalent quantity of lignan (10 S diet) did not alter any measures of bone strength. In contrast to PND 50, bone strength did not differ among groups at PND 132, indicating that the compromise in bone strength was not sustained into early adulthood. Bone size, BMC, and BMD continued to be similar among treatment groups at PND 132. In conclusion, exposing male rats to a diet containing 10% flaxseed or an equivalent quantity of lignan either during lactation only or through to early adulthood is safe with respect to bone health, as measures of bone mass and strength were similar to control rats.
Asunto(s)
Enfermedades del Desarrollo Óseo/etiología , Dieta , Lino/efectos adversos , Lignanos/efectos adversos , Semillas/efectos adversos , Factores de Edad , Análisis de Varianza , Animales , Animales Recién Nacidos , Fenómenos Biomecánicos , Densidad Ósea , Masculino , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
Aberrant crypt foci (ACF) are putative early preneoplastic lesions of colon cancer. To date, many different ACF parameters have been measured as indicators of degree of colon cancer risk. It has been suggested that ACF producing sialomucins (SIM) may be more advanced types of ACF than those producing sulphomucins (SUM), but little data are available to support this. The objective of this experiment was to see if SIM ACF, as observed in whole mount colons, are different from other ACF and surrounding normal colonic crypts in terms of their rate of cell proliferation and degree of dysplasia. Results showed that all ACF had a higher rate of cell proliferation than normal crypts and that SIM ACF had higher cell proliferation in the top regions of the crypt, higher phih index of cell proliferation, higher degree of dysplasia, greater size and increased degree of luminal alterations than SUM ACF. We conclude that SIM ACF, as observed in whole mount colons, have more alterations and are more advanced towards tumorigenesis than SUM ACF and may be a better predictor of colon cancer risk than other measures of ACF.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Coristoma/metabolismo , Neoplasias del Colon/metabolismo , Mucinas/metabolismo , Animales , División Celular , Coristoma/patología , Colon/metabolismo , Colon/patología , Neoplasias del Colon/patología , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Endogámicas F344 , SialomucinasRESUMEN
Based on the reported health benefits of flaxseed, many Canadians are choosing to consume flaxseed or flaxseed-containing foods. However, the safety of exposure to flaxseed during early life such as the suckling period has not been studied, despite the fact that components in flaxseed with potential hormone-like effects can be transferred to nursing offspring via mother's milk. Previous investigations demonstrated that maternal feeding of a 10% flaxseed diet during pregnancy and lactation resulted in estrogenic effects on reproductive indices among male and female offspring. These effects were attributed to the potential estrogenic activity of enterodiol and enterolactone, the two major mammalian lignans that are converted from secoisolariciresinol diglycoside (SDG) in flaxseed by colonic bacteria; however, the effect of exposure to purified SDG at the level of a 10% flaxseed diet was not studied. The objective of this study was to determine whether maternal feeding of flaxseed during lactation altered reproductive indices in male and female offspring. Rat dams were fed basal diet (BD) or BD containing either 100% flaxseed (10F) or the equivalent quantity of SDG present in the 10% (10S) flaxseed diet from the start of lactation until pups were 21 d old. At the end of lactation (postnatal day IPND] 21), suckling pups either continued on the mother's diet or were switched to BD until adolescence (PND 50) or young adulthood (PND 132) to determine if continuous exposure to flaxseed or SDG altered reproductive indices. The reproductive indices that were measured included anogenital distance from birth through PND 21, age and body weight at puberty onset (females only), estrous cycle length, reproductive organ weights at PND 50 and 132, and histological analysis of reproductive organs (uterus, ovaries, prostate) at PND 132. There were no significant effects of exposing male or female offspring to flaxseed or SDG during suckling only or during suckling through the postsuckling period on any of the reproductive indices measured. These findings are in contrast to the estrogenic effects observed in male and female offspring exposed to flaxseed during fetal life through suckling and suggest that fetal life is a more hormone-sensitive period of development. Although maternal feeding of flaxseed during lactation appears to be safe with respect to reproductive indices among offspring, future investigation is required to elucidate whether there are any long-term implications with respect to fertility.
Asunto(s)
Animales Lactantes/crecimiento & desarrollo , Modelos Animales de Enfermedad , Lino/toxicidad , Infertilidad/inducido químicamente , Lactancia/efectos de los fármacos , Lignanos/toxicidad , Exposición Materna/efectos adversos , Reproducción/efectos de los fármacos , Factores de Edad , Análisis de Varianza , Animales , Peso Corporal/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Femenino , Lino/química , Infertilidad/patología , Masculino , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Flaxseed and its lignan secoisolariciresinol diglycoside (SDG) inhibit mammary tumor development in rats. Increased plasma insulin-like growth factor I (IGF-I) concentrations are associated with increased breast cancer risk. Therefore, the effect of flaxseed (5%) or SDG (1.5 mg/day) supplementation on plasma IGF-I levels was examined in rats treated with or without N-methyl-N-nitrosourea (MNU). In MNU-free rats, flaxseed and SDG reduced plasma IGF-I levels, which were inversely related to urinary lignan excretion. Only flaxseed significantly reduced plasma IGF-I concentrations in MNU-treated rats. The anticancer effect of flaxseed and SDG may be related, in part, to reductions in plasma IGF-I.
Asunto(s)
Anticarcinógenos/farmacología , Butileno Glicoles/farmacología , Lino , Glucósidos/farmacología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Carcinógenos/toxicidad , Suplementos Dietéticos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Lignanos/biosíntesis , Lignanos/orina , Glándulas Mamarias Animales/efectos de los fármacos , Metilnitrosourea/toxicidad , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Although chronic exposure to secoisolariciresinol diglycoside (SDG) was shown to alter (3)H-SDG metabolite disposition in rats, the proportion of measured radioactivity attributed to known or unknown SDG metabolites was not determined. Using HPLC and GC-MS, two experiments were conducted to determine the effect of acute (1 d) vs. chronic (10 d) SDG treatment on major urinary metabolites of (3)H-SDG in female, Sprague-Dawley rats (70-72-d-old) over a 48-h period and if new urinary metabolites were detectable in rats fed nonradioactive flaxseed or SDG. A third experiment was conducted to determine changes in postprandial blood levels of (3)H-SDG metabolites over a 24-h period with acute or chronic SDG treatment. Regardless of treatment, enterodiol, enterolactone and secoisolariciresinol accounted for 75-80% of urine radioactivity. Four potential new lignan metabolites, two of which were detected in the urine of rats fed nonradioactive flaxseed or SDG, were found. Type of treatment had no effect on levels of individual urinary metabolites of (3)H-SDG. As observed for plasma lignans in women fed flaxseed, blood radioactivity peaked at 9 h and remained high until 24 h in both treatment groups, suggesting that blood lignan kinetics might be similar with flaxseed or SDG consumption and that they were comparable between humans and rats. In conclusion, the main urinary lignan metabolites were enterodiol, enterolactone and secoisolariciresinol. Urinary composition or blood levels of radioactive lignans were not affected by the duration of SDG exposure. Thus, while chronic SDG exposure alters lignan disposition in rats, it does not change the metabolite profile.
Asunto(s)
Butileno Glicoles/metabolismo , Butileno Glicoles/farmacología , Glucósidos/metabolismo , Glucósidos/farmacología , Lignanos/metabolismo , Análisis de Varianza , Animales , Butileno Glicoles/sangre , Butileno Glicoles/orina , Cromatografía Líquida de Alta Presión , Femenino , Cromatografía de Gases y Espectrometría de Masas , Glucósidos/sangre , Glucósidos/orina , Lignanos/sangre , Lignanos/orina , Periodo Posprandial , Ratas , Ratas Sprague-DawleyRESUMEN
Wheat bran (WB) and its component phytic acid (PA) have both been shown to decrease early biomarkers of colon carcinogenesis, i.e. the PCNA labeling index of cell proliferation and certain aberrant crypt foci parameters. However, it is not known how WB and PA alter other biomarkers of colon cancer risk, such as rate of apoptosis and degree of differentiation, or how they affect colon morphology. Thus, the objectives of this study were to determine the effects of WB on these parameters, to see if PA contributes to these effects and whether there is a difference between endogenous and exogenously added PA. Five groups of azoxymethane-treated male Fischer 344 rats were fed a basal control diet (BD) or BD supplemented with either 25% wheat bran, 25% dephytinized wheat bran (DWB), 25% DWB plus 1.0% PA or 1.0% PA for 100 days. The WB, DWB and PA diets significantly increased the rate of apoptosis and cell differentiation in the whole crypt and the top 40% of the crypt. The WB, DWB and PA diets also significantly increased cell apoptosis in the bottom 60% of the crypt, while all the treatment groups significantly increased cell differentiation versus the BD group in the bottom 60% of the crypt. In addition, the WB, DWB and PA diets decreased the number of crypts per millimeter of colon, while the DWB and PA diets also decreased crypt height measured as number of cells. It is concluded that WB, partly due to its dietary fiber and endogenous PA, and exogenous PA when added to a low fiber diet can increase cell apoptosis and differentiation and favorably affect colon morphology.
Asunto(s)
Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/análisis , Colon/efectos de los fármacos , Fibras de la Dieta/farmacología , Ácido Fítico/farmacología , Animales , Azoximetano , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/metabolismo , Carcinógenos , Diferenciación Celular/efectos de los fármacos , Colon/citología , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/patología , Neoplasias del Colon/prevención & control , Fibras de la Dieta/uso terapéutico , Mucosa Intestinal/citología , Mucosa Intestinal/efectos de los fármacos , Lectinas/análisis , Masculino , Mucinas/biosíntesis , Ácido Fítico/uso terapéutico , Lesiones Precancerosas/inducido químicamente , Lesiones Precancerosas/patología , Antígeno Nuclear de Célula en Proliferación/metabolismo , Ratas , Ratas Endogámicas F344RESUMEN
Previous investigation demonstrated that feeding a 10% flaxseed (10F) diet during pregnancy and lactation enhanced the differentiation of highly proliferative terminal end bud (TEB) structures of rat mammary gland into less proliferative alveolar buds and lobules. From this study, it was hypothesized that the lignan component in flaxseed mediated the observed effects. Because mammary glands with more TEBs are more susceptible to carcinogens, exposure to flaxseed during early postnatal life may reduce the risk of developing mammary cancer. Our objectives were to elucidate whether exposure to flaxseed during lactation only and during pregnancy and lactation can similarly influence the differentiation of mammary gland structures and also to identify whether the lignan component of flaxseed is the biologically active agent. Offspring were exposed to a 10F diet or a dose of purified lignan equivalent to that in a 10F diet (10S) during lactation only or from lactation to postnatal Day 50. Compared with controls, exposure to 10F or 10S during lactation only or from lactation to postnatal Day 50 reduced the number of TEBs and resulted in a rise in the number of alveolar buds. In conclusion, exposure to flaxseed or its purified lignan during lactation is a critical period in which mammary gland development may be promoted by enhancing the differentiation of the mammary gland structures. However, continuous exposure, particularly to purified lignans, resulted in the most differentiation of the mammary gland. The next step is to determine whether the changes in mammary gland structures are chemopreventive in rats challenged with a carcinogen.
Asunto(s)
Anticarcinógenos/farmacología , Butileno Glicoles/farmacología , Lino , Glucósidos/farmacología , Lactancia/efectos de los fármacos , Lignanos/farmacología , Glándulas Mamarias Animales/efectos de los fármacos , Análisis de Varianza , Animales , Butileno Glicoles/administración & dosificación , Femenino , Lino/química , Glucósidos/administración & dosificación , Glándulas Mamarias Animales/anatomía & histología , Neoplasias Mamarias Animales/prevención & control , Embarazo , Distribución Aleatoria , RatasRESUMEN
Reduction of the highly proliferative terminal end bud (TEB) structures in the developing mammary gland by differentiation to alveolar buds (ABs) and lobules has been suggested to be protective against mammary cancer. Flaxseed is high in alpha-linolenic acid (ALA) and secoisolariciresinol diglycoside (SDG). SDG is the precursor of mammalian lignans, which can affect mammary gland structures. Thus, the objective of this study was to determine the effect of lifetime, gestation and lactation or after-weaning exposure to 5 or 10% flaxseed or SDG and flaxseed oil components on the mammary gland structures of virgin female rat offspring at post-natal day 50. Lifetime or gestation and lactation exposure to flaxseed altered mammary gland structure development, whereas exposure to flaxseed after weaning had no effect. Lifetime or gestation and lactation exposure to 5% flaxseed caused endocrine changes, as suggested by delayed puberty onset and reduced number of estrous cycles. These changes reduced exposure to endogenous estrogens, leading to atrophy of mammary TEB structures. SDG, but not flaxseed oil, at the level found in 5% flaxseed produced similar effects as 5% flaxseed. This suggested that the lignans were the component in flaxseed responsible for the observed effects. Lifetime or gestation and lactation exposure to 10% flaxseed also caused endocrine changes, as suggested by early puberty onset and lengthened cycles due to prolonged estrus. This increased exposure to endogenous estrogens and stimulated mammary gland differentiation, as indicated by fewer TEBs and more ABs. Thus, lifetime or gestation and lactation exposure to 5 or 10% flaxseed induced structural changes in the mammary gland that may potentially reduce mammary cancer risk.
Asunto(s)
Anticarcinógenos/farmacología , Butileno Glicoles/farmacología , Lino , Lignanos/farmacología , Glándulas Mamarias Animales/efectos de los fármacos , Neoplasias Mamarias Experimentales/prevención & control , Alimentación Animal , Animales , Anticarcinógenos/uso terapéutico , Butileno Glicoles/uso terapéutico , Relación Dosis-Respuesta a Droga , Estradiol/sangre , Estrógenos , Estro/efectos de los fármacos , Femenino , Lino/química , Lactancia/efectos de los fármacos , Lignanos/uso terapéutico , Aceite de Linaza/farmacología , Aceite de Linaza/uso terapéutico , Glándulas Mamarias Animales/citología , Neoplasias Hormono-Dependientes/prevención & control , Tamaño de los Órganos/efectos de los fármacos , Ovario/efectos de los fármacos , Embarazo , Ratas , Ratas Sprague-Dawley , Maduración Sexual/efectos de los fármacos , Ácido alfa-Linolénico/farmacología , Ácido alfa-Linolénico/uso terapéuticoRESUMEN
Previous studies have shown that the short-chain fatty acids acetate (Ac) and propionate (Pr) enhance the absorption of calcium (Ca) in the rectum and distal colon of humans, with Pr being more effective than Ac. To investigate the effect of Ac and Pr on the kinetics of Ca absorption from the human rectum and distal colon, six healthy subjects were studied. Solutions containing various concentrations of CaCl2.H2O with 56.3 mmol/L Ac, Pr, or NaCl were rectally infused to each subject. Rectal fluid was sampled at the end of the infusion (0 min), and 30 min later colonic contents were collected. Ca absorption for all treatments increased linearly with Ca concentration. For Ca + NaCl, the slope of regression line was 62 mumol.mmol-1.L Ca. With Ac + Ca, the slope of Ca absorption increased significantly to 113 mumol.mmol-1.L Ca, and with Pr + Ca, the slope increased to 159 mumol.mmol-1.L (P = 0.043 versus Ac + Ca) Ac and Pr absorption were increased by Ca. The data suggest that, over a physiologic range of Ca concentration, in the absence or presence of Ac and Pr, Ca is absorbed in the human rectum and distal colon by a non-saturable diffusion process, and that Ca absorption is enhanced by Ac and Pr. The data also suggest that both Ac and Pr absorption is stimulated by Ca.
Asunto(s)
Ácido Acético/administración & dosificación , Calcio de la Dieta/administración & dosificación , Calcio de la Dieta/farmacocinética , Colon/efectos de los fármacos , Colon/metabolismo , Absorción Intestinal/efectos de los fármacos , Absorción Intestinal/fisiología , Propionatos/administración & dosificación , Adulto , Femenino , Humanos , Masculino , Recto/efectos de los fármacos , Recto/metabolismo , SolucionesRESUMEN
We investigated the effect of dietary supplementation with secoisolariciresinol diglycoside (SDG), a lignan precursor isolated from flaxseed, on experimental metastasis of B16BL6 murine melanoma cells in C57BL/6 mice. Four diets were compared: a basal diet (control group) and the basal diet supplemented with SDG at 73, 147 or 293 micromol/kg (equivalent to SDG provided in the 2.5, 5 or 10% flaxseed diet). Mice were fed the diet for 2 weeks before and after an intravenous injection of 0.6 x 10(5) tumor cells. At necropsy, the number and size of tumors that formed in the lungs were determined. The median number of tumors in the control group was 62, and those in the SDG-supplemented groups were 38, 36 and 29, respectively. The last was significantly different from the control (P < 0.01). Dietary supplementation with SDG at 73, 147 and 293 micromol/kg also decreased tumor size (tumor cross-sectional area and volume) in a dose-dependent manner compared with the control values. These results show that SDG reduced pulmonary metastasis of melanoma cells and inhibited the growth of metastatic tumors that formed in the lungs. It is concluded that dietary supplementation with SDG reduces experimental metastasis of melanoma cells in mice.
Asunto(s)
Butileno Glicoles/administración & dosificación , Glucósidos/administración & dosificación , Melanoma/dietoterapia , Melanoma/patología , Neoplasias Cutáneas/dietoterapia , Neoplasias Cutáneas/patología , Animales , Dieta , Relación Dosis-Respuesta a Droga , Ratones , Ratones Endogámicos C57BL , Metástasis de la NeoplasiaRESUMEN
Flaxseed has been shown in previous studies to decrease some early markers of colon cancer risk in part because of its lignans. This study determined whether the intake of flaxseed and lignans is related to the activity of bacterial beta-glucuronidase, an enzyme suggested to increase colon cancer risk. Seven groups of six female rats each were fed, for four weeks, a basal high-fat (20%) diet (BD), BD supplemented with 2.5%, 5.0%, or 10.0% flaxseed, or BD with daily gavage of 0.75, 1.5, or 3.0 mg of secoisolariciresinol diglycoside (SDG), the major mammalian lignan precursor. The specific and total activities of beta-glucuronidase in the cecum were significantly related to the levels of flaxseed (r = 0.539, p < 0.008 and r = 0.599, p < 0.002, respectively) and SDG (r = 0.567, p < 0.007 and r = 0.435, p < 0.04, respectively). The urinary mammalian lignan excretion also increased with increasing flaxseed or SDG levels and thus was significantly related to the specific activity (r = 0.38, p < 0.017) and total activity (r = 0.429, p < 0.007) of beta-glucuronidase. Because flaxseed and lignans are colon cancer protective, it is concluded that, in contrast to other studies, beta-glucuronidase activity may play a beneficial role in their presence by increasing mammalian lignan absorption and enterohepatic circulation.
Asunto(s)
Anticarcinógenos/farmacología , Ciego/enzimología , Lino , Glucuronidasa/metabolismo , Lignanos/farmacología , Semillas , Animales , Anticarcinógenos/farmacocinética , Neoplasias del Ciego/enzimología , Neoplasias del Ciego/patología , Neoplasias del Ciego/prevención & control , Ciego/efectos de los fármacos , Femenino , Lignanos/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
Flaxseed ingestion produces large amounts of mammalian lignans. Since lignans have weak estrogenic/antiestrogenic properties, the objective of this study was to determine in rats whether exposure to 5% or 10% flaxseed affects sex hormone levels and reproductive indices when given at different developmental stages. Rats were exposed to either a basal diet (control), 5%, or 10% flaxseed diet starting at weaning on postnatal day (PND) 21 or continuously from gestation to PND 132 for lifetime exposure. Compared to the control, exposure to 5% or 10% flaxseed after weaning produced no marked reproductive effects, whereas lifetime flaxseed exposure caused significant changes that differed depending on the dose. In female rats, lifetime exposure to 5% flaxseed affected the reproductive tract as indicated by delayed puberty onset. In contrast, lifetime exposure to 10% flaxseed caused earlier puberty onset, higher relative ovarian weight, higher serum estradiol levels, and lengthened estrous cycles. In male rats, lifetime 10% flaxseed exposure raised serum testosterone and estradiol levels and produced higher relative sex organ weights and prostate cell proliferation. In contrast, lifetime exposure to 5% flaxseed reduced adult relative prostate weight and cell proliferation, suggesting potential protection against prostatic disease, although sex hormone levels were unaffected. In conclusion, flaxseed can potentially alter reproduction, depending on the dose and timing of exposure.
Asunto(s)
Estradiol/sangre , Lino , Reproducción/efectos de los fármacos , Semillas , Testosterona/sangre , Animales , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Estro/efectos de los fármacos , Femenino , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ovario/anatomía & histología , Ovario/efectos de los fármacos , Embarazo , Próstata/anatomía & histología , Próstata/citología , Próstata/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: The mammalian lignans enterolactone and enterodiol are produced in the colon by the action of bacteria on the plant precursor secoisolariciresinol diglycoside, which is found in high concentrations in flaxseed. OBJECTIVE: Two experiments were conducted to determine 1) whether there is a dose response in urinary lignan excretion with increasing flaxseed intake, 2) whether flaxseed processing affects lignan excretion, 3) peak plasma lignan concentrations, and 4) plasma lignan concentrations after chronic supplementation. DESIGN: Nine healthy young women supplemented their diets with 5, 15, or 25 g raw or 25 g processed (muffin or bread) flaxseed for 7 d during the follicular phase of their menstrual cycles. Twenty-four-hour urine samples were collected at baseline and on the final day of supplementation. As an adjunct to the 25-g-flaxseed arm, subjects consumed the supplement for an additional day and blood and urine samples were collected at specific intervals. All blood and urine samples were analyzed for enterolactone and enterodiol by gas chromatography-mass spectroscopy. RESULTS: A dose-dependent urinary lignan response to raw flaxseed was observed (r = 0.72, P < 0.001). The processing of flaxseed as a muffin or bread did not affect the quantity of lignan excretion. Plasma lignan concentrations were greater (P < or = 0.05) than baseline by 9 h after flaxseed ingestion (29.35+/-3.69 and 51.75+/-7.49 nmol/L, respectively). The total plasma area under the curve was higher on the eighth than on the first day (1840.15+/-343.02 and 1027.15+/-95.71 nmol x h/L, respectively). CONCLUSION: Mammalian lignan production from flaxseed precursors is dependent on time and dose but not on processing.
Asunto(s)
4-Butirolactona/análogos & derivados , Fibras de la Dieta/farmacología , Lino/metabolismo , Lignanos/metabolismo , Semillas , 4-Butirolactona/sangre , 4-Butirolactona/metabolismo , 4-Butirolactona/orina , Administración Oral , Adulto , Índice de Masa Corporal , Estudios Cruzados , Fibras de la Dieta/administración & dosificación , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Fase Folicular/metabolismo , Cromatografía de Gases y Espectrometría de Masas , Humanos , Lignanos/sangre , Lignanos/orina , Factores de TiempoRESUMEN
Dietary supplementation with flaxseed or its lignan secoisolariciresinol diglycoside (SDG) has reduced dimethylbenz[a]anthracene-induced mammary tumor size and number in rats. The objective of this study was to determine whether flaxseed has a dose-dependent effect on N-methyl-N-nitrosourea (MNU)-induced mammary tumor promotion and whether this effect can be attributed to its SDG. Two days after injection with MNU (50 mg/kg body wt i.p.), female Sprague-Dawley rats were fed a high-fat (20% soybean oil) AIN-93G basal diet alone (BD) or supplemented with flaxseed (2.5% F and 5% F) or SDG by gavage [SDG in 2.5% F (LSDG) and SDG in 5% F (HSDG)] for 22 weeks. Although tumors tended to be smallest in the 5% F group throughout the experimental period, flaxseed feeding did not significantly affect tumor size, multiplicity, or incidence in comparison to BD. However, there was a dose-dependent effect of SDG on tumor multiplicity. Tumor multiplicity was lowest in the HSDG group and highest in the LSDG group throughout treatment (p < 0.05), indicating that HSDG inhibited, whereas LSDG promoted, MNU-induced mammary tumor development. Tumor invasiveness and grade were decreased in all treatment groups compared with the BD (p < 0.032). Thus, although flaxseed feeding had no significant effect on tumor growth indexes, flaxseed and SDG treatment, regardless of dose, appeared to delay the progression of MNU-induced mammary tumorigenesis. Disparities between this study and previous studies on flaxseed may be related to differences in experimental design, the use and dose of a different carcinogen, and protective effects by the alpha-linolenic acid present in the BD.
Asunto(s)
Adenocarcinoma/dietoterapia , Butileno Glicoles/uso terapéutico , Dieta , Lino/uso terapéutico , Glucósidos/uso terapéutico , Neoplasias Mamarias Experimentales/dietoterapia , Fitoterapia , Adenocarcinoma/patología , Animales , Carcinógenos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Lignanos/uso terapéutico , Neoplasias Mamarias Experimentales/patología , Metilnitrosourea , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
The antioxidant activities of the flaxseed lignan secoisolariciresinol diglycoside (SDG) and its mammalian lignan metabolites, enterodiol (ED) and enterolactone (EL), were evaluated in both lipid and aqueous in vitro model systems. All three lignans significantly (p < or = 0.05) inhibited the linoleic acid peroxidation at both 10 and 100 microM over a 24-48 h of incubation at 40 degrees C. In a deoxyribose assay, which evaluates the non site-specific and site-specific Fenton reactant-induced *OH scavenging activity, SDG demonstrated the weakest activity compared to ED and EL at both 10 and 100 microM; the greatest *OH scavenging for ED and EL was observed at 100 microM in both assays. The incubation of pBR322 plasmid DNA with Fenton reagents together with SDG, ED or EL showed that the inhibition of DNA scissions was concentration dependent. The greatest non site-specific activity of lignans was at 100 microM, thus, confirming the results of the deoxyribose test. In contrast, the protective effect of SDG and EL in the site-specific assay was lost and that of ED was minimal. Therefore, the results indicate a structure-activity difference among the three lignans with respect to specific antioxidant efficacy. All three lignans did not exhibit reducing activity compared to ascorbic acid, therefore, did not possess indirect prooxidant activity related to potential changes in redox state of transition metals. The efficacy of SDG and particularly the mammalian lignans ED and EL to act as antioxidants in lipid and aqueous in vitro model systems, at relatively low concentrations (i.e. 100 microM), potentially achievable in vivo, is an evidence of a potential anticarcinogenic mechanism of flaxseed lignan SDG and its mammalian metabolites ED and EL.
Asunto(s)
4-Butirolactona/análogos & derivados , Antioxidantes/química , Butileno Glicoles/química , Glucósidos/química , Lignanos/química , Ácido Linoleico/química , Peroxidación de Lípido , 4-Butirolactona/química , Animales , Butileno Glicoles/aislamiento & purificación , Emulsiones , Estrógenos/química , Lino , Depuradores de Radicales Libres/química , Glucósidos/aislamiento & purificación , Hidróxidos , Mamíferos , Oxidación-Reducción , SemillasRESUMEN
One of the most worrisome possibilities in the field of antimutagenesis and anticarcinogenesis is that factors that protect against one mutagen or carcinogen will not be effective against another. Indeed, such specificities are known. Consequently, protective agents found in experimental screens and systems may not be relevant to the human situation. Additionally, the question of dose is also problematic, because factors that can protect against the levels of mutagens or carcinogens present in the human environment may be overwhelmed by the large dose of the agent used in the experiment, a dose necessitated by the need to have an effect against which protection can be judged. We suggest here that the new technologies available for the measurement of somatic mutation and chromosomal damage can be used to study spontaneous events, thus avoiding both problems.