RESUMEN
Despite recent evidence for an anti-tumour role for high-dose ascorbate, potential mechanisms of action are still unclear. At mM concentrations that are achieved with high-dose intravenous administration, autoxidation of ascorbate can generate cytotoxic levels of H2O2. Ascorbate is also a required co-factor for the hydroxylases that suppress the transcription factor hypoxia-inducible factor (HIF-1). HIF-1 supports an aggressive tumour phenotype and is associated with poor prognosis, and previous studies have shown that optimizing intracellular ascorbate levels down-regulates HIF-1 activation. In this study we have simultaneously measured ascorbate concentrations and the HIF-1 pathway activity in tumour tissue following high dose ascorbate administration, and have studied tumour growth and physiology. Gulo-/- mice, a model of the human ascorbate dependency condition, were implanted with syngeneic Lewis lung tumours, 1g/kg ascorbate was administered into the peritoneum, and ascorbate concentrations were monitored in plasma, liver and tumours. Ascorbate levels peaked within 30min, and although plasma and liver ascorbate returned to baseline within 16h, tumour levels remained elevated for 48h, possibly reflecting increased stability in the hypoxic tumour environment. The expression of HIF-1 and its target proteins was down-regulated with tumour ascorbate uptake. Elevated tumour ascorbate levels could be maintained with daily administration, and HIF-1 and vascular endothelial growth factor protein levels were reduced in these conditions. Increased tumour ascorbate was associated with slowed tumour growth, reduced tumour microvessel density and decreased hypoxia. Alternate day administration of ascorbate resulted in lower tumour levels and did not consistently decrease HIF-1 pathway activity. Levels of sodium-dependent vitamin C transporters 1 and 2 were not clearly associated with ascorbate accumulation by murine tumour cells in vitro or in vivo. Our results support the suppression of the hypoxic response by ascorbate as a plausible mechanism of action of its anti-tumour activity, and this may be useful in a clinical setting.
Asunto(s)
Antineoplásicos/farmacocinética , Antioxidantes/farmacocinética , Ácido Ascórbico/farmacocinética , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Factor A de Crecimiento Endotelial Vascular/genética , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacología , Antioxidantes/metabolismo , Antioxidantes/farmacología , Ácido Ascórbico/sangre , Ácido Ascórbico/farmacología , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patología , Esquema de Medicación , Femenino , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inyecciones Intraperitoneales , Isoenzimas/genética , Isoenzimas/metabolismo , Ratones , Ratones Noqueados , Transducción de Señal , Transportadores de Sodio Acoplados a la Vitamina C/genética , Transportadores de Sodio Acoplados a la Vitamina C/metabolismo , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Inadequate dietary intake of vitamin C results in hypovitaminosis C, defined as a plasma ascorbate concentration ≤23 µmol/L. Our objective was to carry out a retrospective analysis of two vitamin C supplementation studies to determine whether supplementation with 50 mg/day vitamin C is sufficient to restore adequate ascorbate status (≥50 µmol/L) in individuals with hypovitaminosis C. Plasma ascorbate data from 70 young adult males, supplemented with 50 or 200 mg/day vitamin C for up to six weeks, was analyzed. Hypovitaminosis C status was identified based on plasma ascorbate being ≤23 µmol/L and the response of these individuals to vitamin C supplementation was examined. Of the participants consuming 50 mg/day vitamin C for up to six weeks, those with hypovitaminosis C at baseline achieved plasma concentrations of only ~30 µmol/L, whereas the remainder reached ~50 µmol/L. Participants who consumed 200 mg/day vitamin C typically reached saturating concentrations (>65 µmol/L) within one week, while those with hypovitaminosis C required two weeks to reach saturation. Regression modelling indicated that the participants' initial ascorbate status and body weight explained ~30% of the variability in the final ascorbate concentration. Overall, our analysis revealed that supplementation with 50 mg/day vitamin C, which resulted in a total dietary vitamin C intake of 75 mg/day, was insufficient to achieve adequate plasma ascorbate concentrations in individuals with hypovitaminosis C. Furthermore, increased body weight had a negative impact on ascorbate status.
Asunto(s)
Deficiencia de Ácido Ascórbico/tratamiento farmacológico , Ácido Ascórbico/sangre , Ácido Ascórbico/farmacología , Adulto , Ácido Ascórbico/administración & dosificación , Deficiencia de Ácido Ascórbico/sangre , Relación Dosis-Respuesta a Droga , Humanos , MasculinoRESUMEN
Neutrophils are the body's primary defenders against invading pathogens. These cells migrate to loci of infection where they engulf micro-organisms and subject them to an array of reactive oxygen species and antimicrobial proteins to effect killing. Spent neutrophils subsequently undergo apoptosis and are cleared by macrophages, thereby resolving the inflammatory episode. Neutrophils contain high concentrations of vitamin C (ascorbate) and this is thought to be essential for their function. This may be one mechanism whereby vitamin C enhances immune function. The aim of our study was to assess the effect of dietary supplementation with vitamin C-rich SunGold kiwifruit on four important functions of neutrophils: chemotaxis, oxidant generation, extracellular trap formation, and apoptosis. Fourteen young men (aged 18-30 years) with suboptimal plasma vitamin C status (<50 µmol/L) were supplemented for four weeks with two SunGold kiwifruit/day. Plasma vitamin C status was monitored weekly and neutrophil vitamin C levels were assessed at baseline and post-intervention. Neutrophil function assays were carried out on cells isolated at baseline and post-intervention. Plasma vitamin C levels increased to >70 µmol/L (p < 0.001) within one week of supplementation and there was a significant increase in neutrophil vitamin C status following four weeks' intervention (p = 0.016). We observed a significant 20% increase in neutrophil chemotaxis post-intervention (p = 0.041) and also a comparable increase in oxidant generation (p = 0.031). Supplementation did not affect neutrophil extracellular trap formation or spontaneous apoptosis. Our data indicate that supplementation with vitamin C-rich kiwifruit is associated with improvement of important neutrophil functions, which would be expected to translate into enhanced immunity.
Asunto(s)
Actinidia , Ácido Ascórbico/sangre , Quimiotaxis , Frutas , Neutrófilos/citología , Oxidantes/metabolismo , Adolescente , Adulto , Apoptosis , Ácido Ascórbico/administración & dosificación , Dieta , Trampas Extracelulares/metabolismo , Humanos , Masculino , Especies Reactivas de Oxígeno/metabolismo , Adulto JovenRESUMEN
Kiwifruit are a rich source of vitamin C and also contain numerous phytochemicals, such as flavonoids, which may influence the bioavailability of kiwifruit-derived vitamin C. The aim of this study was to compare the relative bioavailability of synthetic versus kiwifruit-derived vitamin C using a randomised cross-over pharmacokinetic study design. Nine non-smoking males (aged 18-35 years) received either a chewable tablet (200 mg vitamin C) or the equivalent dose from gold kiwifruit (Actinidia chinensis var. Sungold). Fasting blood and urine were collected half hourly to hourly over the eight hours following intervention. The ascorbate content of the plasma and urine was determined using HPLC with electrochemical detection. Plasma ascorbate levels increased from 0.5 h after the intervention (P = 0.008). No significant differences in the plasma time-concentration curves were observed between the two interventions (P = 0.645). An estimate of the total increase in plasma ascorbate indicated complete uptake of the ingested vitamin C tablet and kiwifruit-derived vitamin C. There was an increase in urinary ascorbate excretion, relative to urinary creatinine, from two hours post intervention (P < 0.001). There was also a significant difference between the two interventions, with enhanced ascorbate excretion observed in the kiwifruit group (P = 0.016). Urinary excretion was calculated as ~40% and ~50% of the ingested dose from the vitamin C tablet and kiwifruit arms, respectively. Overall, our pharmacokinetic study has shown comparable relative bioavailability of kiwifruit-derived vitamin C and synthetic vitamin C.
Asunto(s)
Actinidia/química , Antioxidantes/farmacocinética , Ácido Ascórbico/farmacocinética , Suplementos Dietéticos , Vitaminas/farmacocinética , Adolescente , Adulto , Antioxidantes/síntesis química , Antioxidantes/metabolismo , Ácido Ascórbico/sangre , Ácido Ascórbico/síntesis química , Ácido Ascórbico/orina , Disponibilidad Biológica , Estudios Cruzados , Ayuno , Flavonoides/farmacología , Frutas/química , Humanos , Masculino , Vitaminas/sangre , Vitaminas/síntesis química , Vitaminas/orina , Adulto JovenRESUMEN
Whether vitamin C from wholefoods has equivalent bioavailability to a purified supplement remains unclear. We have previously showed that kiwifruit provided significantly higher serum and tissue ascorbate levels than synthetic vitamin C in a genetically vitamin C-deficient mouse model, suggesting a synergistic activity of the whole fruit. To determine if these results are translatable to humans, we carried out a randomized human study comparing the bioavailability of vitamin C from kiwifruit with that of a vitamin C tablet of equivalent dosage. Thirty-six young non-smoking adult males were randomized to receive either half a gold kiwifruit (Actinidia Chinensis var. Hort 16A) per day or a comparable vitamin C dose (50 mg) in a chewable tablet for six weeks. Ascorbate was monitored weekly in fasting venous blood and in urine, semen, leukocytes, and skeletal muscle (vastus lateralis) pre- and post-intervention. Dietary intake of vitamin C was monitored using seven day food and beverage records. Participant ascorbate levels increased in plasma (P < 0.001), urine (P < 0.05), mononuclear cells (P < 0.01), neutrophils (P < 0.01) and muscle tissue (P < 0.001) post intervention. There were no significant differences in vitamin C bioavailability between the two intervention groups in any of the fluid, cell or tissue samples tested. Overall, our study showed comparable bioavailability of synthetic and kiwifruit-derived vitamin C.
Asunto(s)
Actinidia/química , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/farmacocinética , Suplementos Dietéticos , Frutas/química , Adolescente , Adulto , Animales , Antioxidantes/administración & dosificación , Ácido Ascórbico/sangre , Ácido Ascórbico/orina , Disponibilidad Biológica , Estudios Cruzados , Humanos , Leucocitos/metabolismo , Masculino , Músculo Esquelético/metabolismo , Semen/metabolismo , Adulto JovenRESUMEN
Enhanced intakes of fruit and vegetables have been associated with improved psychological well-being. We investigated the potential mood-enhancing effects of kiwifruit, a fruit rich in vitamin C and a number of other important micronutrients. Young adult males (n 35) were supplemented with either half or two kiwifruit/d for 6 weeks. Profile of Mood States questionnaires were completed at baseline and following the intervention. No effect on overall mood was observed in the half a kiwifruit/d group; however, a 35 % (P = 0·06) trend towards a decrease in total mood disturbance and a 32 % (P = 0·063) trend towards a decrease in depression were observed in the two kiwifruit/d group. Subgroup analysis indicated that participants with higher baseline mood disturbance exhibited a significant 38 % (P = 0·029) decrease in total mood disturbance, as well as a 38 % (P = 0·048) decrease in fatigue, 31 % (P = 0·024) increase in vigour and a 34 % (P = 0·075) trend towards a decrease in depression, following supplementation with two kiwifruit/d. There was no effect of two kiwifruit/d on the mood scores of participants with lower baseline mood disturbance. Dietary intakes and body status of specific micronutrients indicated a significant increase in the participants' vitamin C intakes and corresponding plasma levels of the vitamin. The results indicate that enhanced intake of kiwifruit by individuals with moderate mood disturbance can improve overall mood.
RESUMEN
BACKGROUND: Humans acquire vitamin C (ascorbate) from their diet, and optimal tissue concentrations are required to maintain its enzyme cofactor and antioxidant activities. How dietary intake affects tissue concentrations is difficult to monitor and has generally been based on the measurement of plasma concentrations. OBJECTIVE: We aimed to determine the effect of various ascorbate intakes on tissue concentrations in the Gulo mouse model of vitamin C deficiency and to compare the effectiveness of delivery when ascorbate was added to the drinking water or obtained through a fruit source (kiwifruit). DESIGN: Gulo(-/-) mice were fed various amounts of ascorbate for 1 mo, either in their drinking water or as a kiwifruit gel. Tissue vitamin C content was measured and compared with concentrations in wild-type mice. RESULTS: Ascorbate concentrations in serum, liver, kidney, heart, and white blood cells were extremely labile and were well below concentrations observed in the wild-type mice when serum concentrations were below saturation. All tissues except for brain were rapidly depleted when intake was stopped. Consumption of a preparation of fresh kiwifruit (either green or gold varieties) resulted in up to 5 times more effective delivery to tissues than when ascorbate was administered via the drinking water. CONCLUSIONS: Subsaturation concentrations of plasma ascorbate resulted in severe deficiency in many tissues, and saturating amounts were required to achieve tissue concentrations similar to those found in wild-type animals. It is possible that the bioavailability of ascorbate is superior from some foods, such as kiwifruit. These results have important implications for human nutrition.