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Rate of excretion of vitamin C in human urine
Abstract
The dosage of vitamin C necessary to maintain a level in the urine which could be detected using the 2,6-dichlorophenolindophenol
assay was determined with undergraduate students. Students taking 250 mg daily did not excrete significant levels of vitamin
C in their urine, while excretion increased at doses from 0.5 to 2 g. A 2 g daily dose caused detectable excretion from about
4 until 16 hr later, on both the first and eighth day. A dose of 500 mg taken every 12 hr led to continuously-detectable levels
of vitamin C in the urine. The conclusion is that two conditions are necessary to elevate vitamin c excretion continuously:
a dose of at least 500 mg and a dose every 12 hr. This is substantially higher than the U.S. recommended daily allowance and
more frequent than administration being used in clinical trials.
... The measurement of ascorbate in urine is generally more appealing as urine collection is fast and noninvasive. Indeed, the presence of ascorbate in human urine has been shown to be a useful, non-invasive dietary, fruit or vitamin C intake biomarker [7][8][9]. Recently it has been shown that ascorbate levels in urine can be used to facilitate the detection of precancerous adenomatous colorectal polyps. ...
... The absolute concentrations of ascorbate in urine 1.5-10 h postingestion of a 500 mg vitamin C tablet, as measured by NMR are plotted in Fig. 7a. Previously, it was reported that urine concentrations of ascorbate typically peak around 4 h after ingestion of a vitamin C tablet and that ascorbate levels return to baseline levels about 12 h later [9,24]. As seen in Fig. 7a, our results are slightly different, with greater than 1000 μM ascorbate detected at all times points except after the 1.5 h time point. ...
... However, as seen in Fig. 7b, when the ascorbate concentrations are normalized to creatinine, the time-course results are somewhat more aligned with what would be expected. Overall, the time course data shown in Fig. 7b parallel those of [9,24] where our urinary ascorbate concentrations peaked 5.5 h and started to return to baseline at 10 h post-ingestion. In our study, a 500 mg vitamin C tablet was ingested while in the former studies, a 200 mg vitamin C tablet was consumed. ...
The presence of ascorbate in human urine has been shown to be a useful dietary, fruit or vitamin C intake biomarker. More recently it has been discovered that ascorbate levels in urine can be used to facilitate the detection of precancerous colorectal polyps. While there are a number elaborate HPLC, MS or multi-step enzymatic "kit" methods to detect and quantify urinary ascorbate, these are time consuming and expensive. There are also a number of low-cost paper-based ascorbate detection dipsticks. However, the limits of detection and quantification accuracy for these dipsticks are not adequate for applications with human urine. To address these limitations, we have developed a fast, sensitive, single-step colorimetric assay that can be used to quantify ascorbate in urine and other biological fluids. The assay uses the tetrazolium salt, methylthiazolyldiphenyl-tetrazolium bromide (MTT), with the electron carrier phenazine methosulfate (PMS), in a chelated acidic phosphate-buffer to produce a vivid purple color in the presence of ascorbate. Confirmation of the performance of the assay and of its standard curve in human urine was also done using independent LC-MS/MS and NMR analyses. The lower limit of detection of the ascorbate dipstick assay described here was found to be 3.2 μM. The paper dipsticks are stable over a wide range of temperatures and can be stored for up to 150-days.
... When Lamm was publishing his megavitamin protocol, he was unaware of Ordman's discovery [15] that AA must be taken twice a day (BID) to maintain elevated levels in the serum, a result we showed next for calcium [16] and eventually assumed for all water-soluble nutrients. In 1994, we published in AGE [15] that when people consume AA orally, AA intake above 500 mg is excreted in the urine over 12 hr, and that 500 mg must be consumed twice a day to guarantee continuous excretion of excess in the urine (Figure 2). ...
... When Lamm was publishing his megavitamin protocol, he was unaware of Ordman's discovery [15] that AA must be taken twice a day (BID) to maintain elevated levels in the serum, a result we showed next for calcium [16] and eventually assumed for all water-soluble nutrients. In 1994, we published in AGE [15] that when people consume AA orally, AA intake above 500 mg is excreted in the urine over 12 hr, and that 500 mg must be consumed twice a day to guarantee continuous excretion of excess in the urine (Figure 2). Levine [9] showed the relationship between oral AA dosage and serum levels, confirming Ordman's conclusion that 500 mg AA BID produces the highest statistically significant serum concentration of Vitamin C [AA] in people. ...
... Taking 2 g AA raises the concentration of AA filtered by the kidneys to a maximum of approximately 6 mM. Our previous work [15] demonstrated that when AA is taken orally, the concentration in urine rises over 4 hr, remains elevated for the next 12 hr, and then falls rapidly, unless another dose of AA has been consumed. A single daily dose of 2 g will elevate the bladder concentration for at most 12 hr. ...
Background: Continuous exposure to millimolar (mM) Vitamin C (AA) in vitro kills cancer cells. For superficial bladder carcinoma (SBC), standard chemotherapy is instillation of Bacillus Cal-mette-Guerin. The recurrence rate with this therapy is 91%. But high dosage vitamins including AA reduced the recurrence to 41%. Aim: To determine the oral dosage of AA that causes the highest concentration of AA [AA] in the bladder. Method: We conducted a clinical trial of 14 people who took various dosages of AA, and analyzed the [AA] in their urine. Results: AA above 2 g twice a day was not absorbed. But that intake produced a bladder [AA] above 1 mM in all participants. Conclusion: Taking 2 g of AA BID will increase [AA] in the bladder to a level likely to kill cancer cells that cause SBC. Taking that dosage 2 consecutive days a week is likely to reduce the recurrence rate of SBC substantially.
... Because most of a high dose of AA is excreted over 12 h (King et al. 1994), it is important to control the time between tablet consumption and in vivo sampling. The first measurable endpoint used to determine a pharmacological dosage for AA was urinary excretion (King et al. 1994), which demonstrated that 500 mg of oral AA is absorbed over 4 h and excreted over the next 12 h. ...
... Because most of a high dose of AA is excreted over 12 h (King et al. 1994), it is important to control the time between tablet consumption and in vivo sampling. The first measurable endpoint used to determine a pharmacological dosage for AA was urinary excretion (King et al. 1994), which demonstrated that 500 mg of oral AA is absorbed over 4 h and excreted over the next 12 h. It has been found that large oral doses of other water-soluble nutrients, such as calcium (Cone et al. 1996), are also excreted over 12 h. ...
... Participants were asked to resume their personal dietary patterns without supplements for 6 days between regimens. This is sufficient to restore AA to unsupplemented levels (King et al. 1994). As AT supplementation was invariable among regimens, baseline levels were not determined. ...
Some clinical trials of vitamins C and E have neglected important design features. Our objective was to demonstrate a detailed design that includes essential elements for an effective study of these vitamins in vivo. While taking 400 IU (international units) of vitamin E, subjects took different dosages of vitamin C during three distinct periods. Dosages were 200 mg in food, 500 mg as supplements twice a day (500 × 2), and 1,000 mg as supplements twice a day (1000 × 2). Ten participants spent 3 weeks at each dosage before plasma was drawn on two consecutive days. Final samples were taken after a week with no supplementation. Selected by investigators at four institutions, endpoints were protein carbonyls, TBARs (thiobarbituric reactive substances), and Heinz body formation in RBCs (red blood cells). TBARs and protein carbonyls did not change significantly with dosage. However, Heinz body formation increased at either higher or lower intakes of vitamin C. Even with daily vitamin E, Heinz bodies were significantly fewer at 500 × 2. Results indicate that even with 400 IU vitamin E daily, it is possible to distinguish the effect of different levels of vitamin C with Heinz bodies. This effect may be due to pro-oxidant action of vitamin C or to prolonged survival of RBCs.
... In this case, VC has a half-life of about 30 min [21][22][23]. King et al. [24] discovered that 500 mg of VC taken orally every 12 hrs is sufficient to provide continuous excretion of excess VC into the urine, but high dose consumption once a day caused detectable excretion from about 4 to 16 hrs later. VC is a potent antioxidant that reduces oxidative stress and enhances endothelial function by scavenging intracellular superoxide, thereby activating smooth muscle guanylyl cyclase and eNOS, which leads to the production of NO [25]. ...
The lowering blood pressure effect of vitamin C (VC) has been evaluated in various models. As VC has a fast degradation rate in the body after consumption, a study of the frequency-dependent manner of VC is essential for the sustained antihypertension effect of VC. In this study, we investigated the frequency and dose dependency of vitamin C (VC) on blood pressure reduction in spontaneously hypertensive rats (SHRs). Wistar–Kyoto rats (WKYs) and SHRs were orally administered tap water or VC (250, 500, 1000, and 2000 mg/60 kg/day). Blood pressures were measured using the tail-cuff method, and thoracic aortas, liver, and blood were harvested from sacrificed rats after 8 weeks to measure angiotensinogen, angiotensin-converting enzyme (ACE) I, endothelial nitric oxide synthase (eNOS), and total nitric oxide (NOx) concentration. VC decreased blood pressure from the fourth week with no significant differences between doses. The twice-a-day administration of VC decreased blood pressure from the second week, and the blood pressure in these groups was close to that of the WKY group in the eighth week. Treatment with once a day VC decreased ACE I production which was further significantly reduced in twice a day groups. Angiotensinogen and eNOS production were increased upon VC treatment but were not significant among groups. The NOx content was decreased by VC treatment. These results suggest that VC lowers blood pressure in SHRs by directly targeting ACE I production in a frequency-dependent manner and may improve endothelial function depending on the frequency of administration.
... "[A] wide range of pharmacological activity including antioxidant, hepatoprotective, brain protective, anti-diabetic, analgesic, spasmolytic, immunosuppressant, anti-platelet, gastroprotective, cytoprotective, laxative, estrogenic, diuretic, hypotensive, antibacterial and antifungal activities have been exhibited for this plant in modern medicine" [23] [24]. Based on the work of Ordman [10], 500 mg of vitamin C twice a day will maintain near its highest concentration in people's blood. There are numerous likely benefits. ...
... The model used by Ralli et al (1) to describe the renal excretion of ascorbic acid is discussed below. This model is based on the knowledge that ascorbic acid is not bound to plasma proteins (2) and is filtered and actively reabsorbed in the renal tubules by a saturable process, as shown in Figure Al. ...
Ascorbic acid (vitamin C) is commonly used as a dietary supplement, often in megadoses. However, as the daily oral dose is increased, the concentration of ascorbic acid in the plasma and other body fluids does not increase proportionally, but instead tends to approach an upper limit. For example, when the daily dose is increased from 200 to 2500 mg (from 1.1 to 14.2 mmol) the mean steady state plasma concentration increases only from approximately 12 to 15 mg/L (from 68.1 to 85.2 mumol/L). Published data were reanalyzed with an integrated modeling approach to shed new quantitative light on this phenomenon. This analysis is based on the renal clearance of ascorbic acid, which rises sharply with increasing plasma concentrations as a result of saturable tubular reabsorption. The analysis indicates that both saturable gastrointestinal absorption and nonlinear renal clearance act additively to produce the ceiling effect in plasma concentrations. As a consequence of this ceiling effect, there is no pharmacokinetic justification for the use of megadoses of ascorbic acid.
... Together with glutathione, ascorbic acid is an important reserve of reducing capacity and is accumulated to a certain extent in the body. However, excessive amounts are immediately eliminated so it is important to have a continuous intake of vitamin C with the diet (King et al. 1994;Padayatty et al. 2003). Vitamin E is instead the principal vitamin with a lipophilic structure and for this reason it is indispensable for protection of the cellular membranes and other subcellular lipid structures. ...
In recent years, the sensitivity of consumers and producers towards the environment and health topics has increased significantly, and these issues are involving more and more the agricultural world. Much has been done in terms of cropping systems and technology, but the issues relating to the quality and nutritional value of products turn out to be more complex and sensitive. In this regard, the consumer is more aware of these issues thanks to the many suggestions offered daily both in the health and in a healthy diet.
In this sense, this chapter aims to provide a current status of the concept of quality in the context of vegetable products and highlight its importance especially in order to promote vegetables by improving the final consumer diet. In this regard, the indicative pattern of the chapter could include three main sections. The first concerns about the identification and exploration of the quality concept and its evolution over time with respect to all aspects that contribute to its perception by the consumer. Moreover the technical-agronomic factors and environmental factors that determine the product quality associated with pre-harvest until the ripening stage will be considered. Finally, in the last section of this chapter, we will refer to the quality maintenance in post-harvest considering the evolution of multiple physiological aspects (antioxidants, phenols, vitamins, macro- and micronutrients, etc.) to the hypothetical purchase of the product by the consumer. During all the steps described so far, in which quality is involved, we will consider the potential health traits and benefits relevant to the health of the consumer trying to provide a clear and complete view in this research field.
... The first biomarker for long-term optimal dosage was published in 1994. King et al. [3] discovered that 500 mg of AA taken orally every 12 hr are sufficient to provide continuous excretion of excess AA into the urine. In 1996, a similar study by Levine M et al. [4] confirmed those results, showing that that dosage provides the highest statistically significant concentration in plasma for protection from free radical damage. ...
This review provides information determining how much vitamin C to take, including analysis of the recent findings, which demonstrate ad-vantages and problems with higher daily doses. The Daily Value for vitamin C was raised to 90 mg for men in 2000, and Upper Limit of 2,000 mg per day was established as being safe. This followed a study of urinary excretion of vitamin C (AA) that demonstrated 500 mg twice a day provides levels sufficient to cause continuous urinary excretion in humans. That is the lowest oral dosage evaluated that significantly satu-rates blood plasma. A later study endorsed 200 mg from dietary sources for the RDA. Even though plasma concentration of AA is then sig-nificantly lower, at 200 mg daily certain white blood cells are saturated with AA. Recently many studies have indicated the benefit of high levels of AA to maintain the brain, bones, and heart, reduce damage from stroke, brain trauma, and cataracts, and lower the risk of cancer me-tastasis and colds. Pro-oxidant activity has been found only for i.v. adminstration, where high concentrations appear effective destroying tumor cells while not harming normal cells. This review evaluates recent research and finds it consistent with the hypothesis that people, es-pecially older people and soldiers in combat environments, are likely to benefit if they main-tain the saturating level of AA by taking 500mg supplements twice a day.
... The model used by Ralli et al (1) to describe the renal excretion of ascorbic acid is discussed below. This model is based on the knowledge that ascorbic acid is not bound to plasma proteins (2) and is filtered and actively reabsorbed in the renal tubules by a saturable process, as shown in Figure Al. ...
Ascorbic acid (vitamin C) is commonly used as a dietary supplement, often in megadoses. However, as the daily oral dose is increased, the concentration of ascorbic acid in the plasma and other body fluids does not increase proportionally, but instead tends to approach an upper limit. For example, when the daily dose is increased from 200 to 2500 mg (from 1.1 to 14.2 mmol) the mean steady state plasma concentration increases only from approximately 12 to 15 mg/L (from 68.1 to 85.2 mumol/L). Published data were reanalyzed with an integrated modeling approach to shed new quantitative light on this phenomenon. This analysis is based on the renal clearance of ascorbic acid, which rises sharply with increasing plasma concentrations as a result of saturable tubular reabsorption. The analysis indicates that both saturable gastrointestinal absorption and nonlinear renal clearance act additively to produce the ceiling effect in plasma concentrations. As a consequence of this ceiling effect, there is no pharmacokinetic justification for the use of megadoses of ascorbic acid.
The national effort to reduce the incidence and severity of cancer and other chronic diseases in the United States has suffered from political influences that undermine the interests of the public. As one example, the medical profession has not made adequate use of nutritional information to improve the health of the population. Daily values for vitamins were established in the United States during World War II, when the goal was to avoid short‐term deficiencies so soldiers could continue to fight. But there is more to health than short‐term survival. Linus Pauling advocated megadoses of vitamin C to reduce the risk of cancer and to improve long‐term health. Despite numerous studies demonstrating that better nutrition and exercise are vital to a longer span of good health, the U.S. Food and Drug Administration (FDA) does not permit claims to be made about the health benefits of specific nutritional supplements. The FDA is responsive to political pressures, including pressures to reduce public knowledge of supplements and their benefits. Pharmaceutical companies contribute to members of Congress to influence health policy. Those companies promote legislation and regulations that favor the use of expensive medical treatments and that limit the provision of cost‐effective public health measures. This article reviews many examples of failures of our current medical system, and methods that could prevent the current expense and suffering in this nation.
L-ascorbic acid (ascorbate or vitamin C) is a required nutrient for humans. Absorption, transport, and disposition of ingested ascorbate involve the following: (1) bioavailability and absorption in the gastrointestinal tract; (2) presence in the circulation; (3) tissue distribution; (4) excretion; and, (5) metabolism. Fundamental to each of the above are ascorbate chemistry and mechanisms of transport of ascorbate across membranes. Ascorbate can be reversibly oxidized to dehydroascorbic acid, which can be irreversible degraded. Both reduced and oxidized forms cross cell membranes. Differences in transport kinetics, tissue specificity, and Na+ and energy dependence strongly support the existence of separate transport mechanisms. An important consideration in the analysis of ascorbate transport iss that of substrate availability. Reduced ascorbate is by far the most predominant form found in plasma and tissues. Dehydroascorbic acid is rapidly reduced intracellularly to ascorbate by both enzymatic and chemical mechanisms. Despite constitutively low levels of dehydroascorbic acid, conditions that promote oxidation of ascorbate can profound alter both the nature and availability of substrate. Elucidation of mechanisms that modulate the delivery of ascorbate to tissues and its utilization under different metabolic conditions will be invaluable for making recommendations for ascorbate ingestion. Published by Elsevier science Inc. 1998.
Even though a certain part of oxalate in the urine derives from metabolized ascorbic acid (AA), the intake of high doses of vitamin C does not increase the risk of calcium oxalate kidney stones due to physiological regulatory factor: gastrointestinal absorption as well as renal tubular reabsorption of AA are saturable processes, and the metabolic transformation of AA to oxalate is limited as well. Older assays for urinary oxalate favored in vitro conversion of AA to oxalate during storage and processing of the samples. Recurrent stone formers and patients with renal failure who have a defect in AA or oxalate metabolism should restrict daily vitamin C intakes to approximately 100 mg. But in the large-scale Harvard Prospective Health Professional Follow-Up Study, those groups in the highest quintile of vitamin C intake (> 1,500 mg/day) had a lower risk of kidney stones than the groups in the lowest quintiles.
Ascorbate breakdown reportedly accounts for 30% to 55% of urinary oxalate excreted. Three potential degradation routes can be postulated: bowel, endogenous, and urinary. Because the pH of normal urine ranges from 4.5 to 8.0, the urinary oxalate concentration in the presence of ascorbate may be influenced by urinary pH and environment, so we studied ascorbate conversion to oxalate in standard buffer solution and in urine. About 10% of infection stones associated with Proteus mirabilis are reportedly composed of calcium oxalate, and their pathogenesis is not well explained. Therefore, we studied whether a pH change induced by P. mirabilis contributes to ascorbate conversion to oxalate in vitro.
Oxalate production from ascorbate increased as a function of pH (7.0-10.0) and incubation time (30 minutes-24 hours) in standard and urine specimens. Two-hour exposure to pH 10 in a urinary milieu containing approximately 3 mM ascorbate converted approximately 40% of the ascorbate to oxalate, whereas 24-hour exposure to pH 8 in a urinary milieu that was approximately 3 mM ascorbate converted approximately 20% of the ascorbate to oxalate. The pH in Proteus cultures increased to 9.0 at 24 hours of culture. The ascorbate concentration in the culture medium significantly decreased at 12 hours and 24 hours, and the oxalate concentration increased significantly at 24 hours.
Urinary ascorbate, if present at a high concentration in association with Proteus mirabilis infection, appears to be locally degraded to oxalate, potentially leading to calcium oxalate deposition on infection stones.
The popularity of vitamin C can be attributed to Linus Pauling who, in the 1970s, recommended the use of vitamin C for the prevention of influenza. Vitamin C has subsequently been used extensively in a wide range of diseases. Ascorbic acid (vitamin C) has been incriminated as a possible risk factor for calcium oxalate stones due to its enzymatic conversion into oxalate. However, this lithogenic role has never been clearly established. Studies evaluating the effect of ascorbic acid on lithogenesis have reported contradictory results. Ascorbic acid has also been extensively used as an urine acidifier for the treatment of chronic or recurrent urinary tract infection. Once again, the data of the literature are contradictory. The purpose of this article was to review the effects of ascorbic acid on lithogenesis and urinary pH based on a review of the literature.
This is a review of the most relevant articles on the vitamin C-based therapy with emphasis to high per os and parenteral doses that might be effective on calories utilization, energy production, mythocondrial red-ox function, gene expression and metabolism. Ascorbic acid treatment in tumor bearing patients is a puzzling issue whose rationale is based on low vitamin plasma concentration and cancer uptake and sequestration; furthermore high parenteral dosages should be required to achieve a putative oxidative damage on tumor DNA, by this antioxidant molecule; thus bioavailability and metabolism as well as clinical effectiveness are reviewed on the basis of the evidence based medicine: specific evidence of vitamin C efficacy is quite limited, but areas like diabetic vascular complications and sideropenia might benefit of the treatment; high parenteral doses might be useful, perspectively also in relapsing urinary tract infection, after conventional treatment failure, due to the high output of ascorbic acid and potential saturation of the target tissues.
The present study was undertaken to explore the association between vitamin C nutritional status in pregnant women with premature rupture of the chorioamniotic membranes (PRM). A case-control cross-sectional study was carried out in 10 women with PRM and 19 women without PRM. The women were evaluated in the first hours postpartum while hospitalized: 10 ml of blood were obtained from each woman to determine vitamin C expressed as micrograms/10(8) leucocytes or microgram/mg of leucocyte protein. Data on fruit and vegetable consumption was collected by a frequency dietary survey and the hospital clinical records were reviewed to obtain their obstetric history and data on the presence of infection during pregnancy, in placenta and/or in fetal membranes. Low vitamin C levels were considered at a cut-off point equal or less than 26.33 micrograms/10(8) leucocytic cells and 3.15 micrograms/mg leucocyte protein. An association was found between low vitamin C levels and cases with PRM. No difference was found in the frequency of consumption of fruit and vegetables between the two groups. Infections were more frequently found in the PRM group, when the women had low levels of vitamin C, and when both risk factors were present simultaneously the proportion of PRM cases identified was greater than 0.75.
The oxidation of methyl linoleate in solution initiated with azo compounds has been studied in the absence and presence of vitamin E and vitamin C. Both vitamin E and vitamin C acted as a chain-breaking antioxidant and they suppressed the oxidation and produced an induction period. The inhibition rate constant for the scavenging of peroxy radical was calculated at 37 degrees C as kinh = 5.1 X 10(5) M-1 s-1 and 7.5 X 10(4) M-1 s-1 for vitamin E and vitamin C, respectively. It was suggested that each vitamin E could trap two peroxy radicals, whereas vitamin C could trap only one peroxy radical under the reaction conditions employed in this study. When both vitamin E and vitamin C were present, the oxidation was suppressed quite efficiently and the apparent inhibition rate constant was obtained as kinh = 4.0 X 10(5) M-1 s-1. Furthermore, vitamin E remained almost unchanged and only vitamin C was consumed at the initial stage and vitamin E was consumed after vitamin C was exhausted. It was concluded that vitamin E trapped the peroxy radical and the resulting alpha-chromanoxy radical reacted with vitamin C to regenerate vitamin E.
The biological function of vitamin E as a lipid antioxidant has been a topic of research for over twenty years since the discovery of its antioxidant activity by Olcott and Mattill and their subsequent review of these properties. This biological essential of a lipid antioxidant is mainly filled by vitamin E. Therefore, the chemical basis of vitamin E function is its reactions with free radical intermediates of lipid peroxidation and with the peroxides. The tocopherols have many interesting and complex oxidations; there are unfortunately too few studies of these reactions and their involvement in vivo. This chapter discusses mechanism of free radical damage and cellular damage caused by lipid peroxidation. The chapter also outlines the interrelationships of sulphur amino acids, vitamin E, and free radical peroxidation. Finally, the chapter considers the biological and antioxidant activity of selenium.
A short while later, Dr. Kamin sent us another commentary about the crucial vitamin question. It was prepared for the newsletter of the American Institute of Nutrition, Nutrition Notes. Since the notes are not copyrighted and reproduction privileges are offered by the publisher of Nutrition Notes, this commentary is the public domain. It sheds light on what seems to be the thorniest issue in this episode of the dispute.
This review includes current information on advances regarding the chemistry and synthesis of L-ascorbic acid, highlighting its importance in nutrition, health, food processing (enzymatic browning, meat preservation, beer manufacture, wine production, dairy products, fats and oils, flour and dough improvement), plant and animal applications, and industrial applications.
Oxidative damage to DNA, proteins and lipids appears to be a major contributing factor in aging and the degenerative processes
that accompany it, including cancer, heart disease, cataracts, and cognitive dysfunction. Numerous epidemiologic studies have
found that persons with lower intake of antioxidant nutrients or the fruits and vegetables that provide them have a higher
risk of almost every type of cancer. In many studies, those with low intake had twice the risk of those with high intake.
A large-scale follow-up study found that persons with a low vitamin C intake had a statistically significantly higher risk
of heart disease mortality and total mortality over the subsequent 10 years. In addition, several studies have found that
persons with low intake of antioxidant nutrients such as vitamin C and carotene had significantly increased risk of developing
age-related eye diseases such as cataracts. Although many older people consume more antioxidants than younger people, very
substantial proportions of older persons have very low intakes and blood levels. Among white men 65–74 in the U.S., 15% have
blood ascorbate levels below 0.4 mg/dl, the lower boundary of “normal.” Among black men of that age, 25% have levels below
0.4 mg/dl.
Persons with high intakes of dietary vitamin C or citrus fruit have repeatedly been found to have a lower risk of developing
cancer. In addition, recent research indicates an important role in heart disease and other disabilities of aging. This paper
will summarize the epidemiologic literature briefly, and provide data on intake of this vitamin in the United States.
Vitamin C has numerous biologic functions, including collagen, hormone and neurotransmitter synthesis. Its role as an antioxidant
and free radical scavenger may be of primary importance in many of its roles in disease prevention. Oxidative and free radical
damage to DNA and cell membranes is an important factor in cancer initiation, and it is clear that ascorbic acid can help
prevent such damage.
The in vivo effect of ascorbic acid on human natural killer (NK) cell activity was determined. Twenty control healthy subjects were given ascorbic acid at a concentration of 60 mg/kg, and blood was drawn at 0,1,2,4,8, 24 and 48 hours after treatment with ascorbic acid. Peripheral Blood Lymphocyte-NK activity was measured by a 4-hr.-51Cr-release assay using K562 tumor cells as targets. Treatment with ascorbic acid was shown to have a biphasic effect on NK activity: a transient slight suppression between 1 to 2 hrs. (20% of control) was followed by a significant enhancement (an over-shoot) at 8 hrs. that was further increased at 24 hrs., then the activity returned to the normal level by 48 hrs. Changes in the activity of ascorbate treated NK cells were inversely related to the E:T ratio; namely 231%, 189%, 141% and 127% at 6:1, 12:1, 25:1 and 50:1 E:T ratio respectively. Flow cytometry analysis indicated no quantitative changes in the NK cell sub-populations post treatment with ascorbic acid in the experimental subjects as compared with control untreated subjects. Simultaneous to measurement of NK count and activity, ascorbic acid and its uptake by PBL was measured in the plasma. The uptake of the vitamin was maximized at 2–4 hours and maintained at a high level up to 24 hours. We conclude that ascorbic acid is a potent immunomodulator and its effect in enhancement of NK cytotoxicity may explain one mechanism by which ascorbic acid exerts its probable anti cancer activity.
— Mechanisms for the initiation of free radical reactions in vivo are reviewed, including ozone and 1O2 reactions, radiation, one-electron transfer processes, and enzymatic reactions. The roles that radical reactions might play in aging processes and in carcinogenesis are discussed.
This chapter discusses selected methods for the determination of ascorbic acid in animal cells, tissues, and fluids. Methods for determining ascorbic acid are numerous. In general, chemical analyses for the vitamin are divided into two groups; the determination of the reduced form and the determination of the oxidized form. The former group of analyses is usually based upon the oxidation–reduction properties of ascorbic acid. These are widely used as the fundamental reactions in the measurement of vitamin C. The latter group of analyses is usually based upon the oxidation of the ascorbic acid and the subsequent formation of a hydrazone or a fluorophore. Best results are obtained if samples, especially plasma, are quickly stabilized with either trichloroacetic acid or metaphosphoric acid and immediately analyzed. Prompt stabilization is especially important in the case of plasma or serum. The greater stability of ascorbic acid in acid solution is because of the decreased tendency for the hydrolysis of the lactone ring with decreasing pH.
The effects of dietary ascorbic acid on plasma lipoprotein and liver lipid peroxide concentrations were examined using ODS od/od rats with a genetic defect in the ability to synthesize ascorbic acid. ODS od/od rats were fed purified diets supplemented with 0 to 300 mg ascorbic acid/kg diet for 21 d. An ascorbic acid-free diet induced body weight loss, depleted ascorbic acid in the plasma and increased thiobarbituric acid-reactive substances in the plasma and liver as compared with rats fed ascorbic acid supplemented diets and with normal ODS +/+ rats fed the ascorbic acid-free diet. Increasing ascorbic acid concentration in the diet inhibited the development of these ascorbic acid deficiency symptoms in a dose-dependent manner. The dietary requirement of ascorbic acid to maintain normal body weight gain and plasma lipid peroxide concentrations was approximately 150 mg ascorbic acid/kg diet. On the other hand, even 300 mg ascorbic acid/kg diet was insufficient to maintain a hepatic concentration of ascorbic acid comparable to that in the liver of ODS +/+ rats. The lipid peroxide concentration in plasma LDL and liver was significantly elevated in ODS od/od rats fed the ascorbic acid-free diet. Supplementing the diet with 300 mg ascorbic acid/kg kept those concentrations within the normal ranges seen in the ODS +/+ rats.
The effect of ascorbic acid deficiency on serum and liver cholesterol, phospholipid and triglyceride levels, serum lipoprotein levels and serum lipoprotein cholesterol levels were examined in male rats with a hereditary defect in ascorbic acid synthesis (ODS rats). Male homozygotes (od/od) and male rats of their parent strain (+/+) were each divided into four treatment groups and were fed vitamin C-deficient or vitamin C-replete diets containing either 0 or 0.5% cholesterol. During the 3-wk feeding-period the ODS (od/od) rats fed the vitamin C-deficient diet gradually decreased food intake, resulting in a lower body weight than that of od/od rats given ascorbic acid. The serum cholesterol level was significantly higher in the vitamin C-deficient od/od rats fed the cholesterol diet, and it tended to be higher in those fed the control (0% cholesterol) diet, whereas the liver lipid levels remained unchanged relative to those in od/od rats fed the vitamin C-replete diet. The serum very low density lipoprotein and high density lipoprotein (HDL) cholesterol levels were lower in od/od rats fed the vitamin C-deficient diet without cholesterol, but intermediate density lipoprotein and low density lipoprotein cholesterol levels were markedly higher in the vitamin C-deficient od/od rats than in od/od rats given ascorbic acid, regardless of dietary cholesterol level. The ratio of HDL2 cholesterol to HDL3 cholesterol was also higher in the vitamin C-deficient od/od rats. The parent strain of the od/od rats (+/+) showed no change due to vitamin C deficiency. These results suggest that vitamin C deficiency delays low density lipoprotein metabolism and produces hypercholesterolemia in male od/od rats.
THE NATIONAL CANCER Institute is taking a look at the biologic functions of ascorbic acid, beginning with a 3-day symposium that Nobelist Linus Pauling, PhD, Palo Alto, Calif, says revealed "an astonishing amount of information bearing on ascorbic acid and its relation to cancer; I didn't realize there was so much." The institute's Gladys Block, PhD, says a number of the symposium reports on ascorbic acid's effects on animals and in cell cultures are worth pursuing. She notes a suggested role for ascorbate as an adjuvant to conventional cancer therapy and to reduce toxicity. One move in this direction is to ask the investigators to return to Bethesda, Md, site of the institute and symposium, for additional discussion of their work. The symposium had its genesis in a meeting 18 months ago between Pauling and the National Cancer Institute's director, Samuel Broder, MD. Among results of that meeting, Pauling says
The pharmacokinetics of vitamin C following a 500 mg oral tablet dose were compared in a group of fourteen healthy young women whose age was 26.0 +/- 2.8 years (mean +/- s.d.), and in a group of fourteen healthy elderly women aged 68.1 +/- 2.6 years. The body composition of each subject was assessed using several anthropometric measurements in order to help explain any observed differences in the pharmacokinetic behavior of vitamin C. The vitamin C doses were characterized with the subjects in two states of vitamin C nutriture: a 'depleted' state which was achieved by 4-5 weeks on a vitamin C-restricted diet of less than 10 mg/d and a 'supplemented' state in which the subjects were given daily doses of 500 mg of vitamin C for 3 weeks. Plasma and urine samples were collected for 72 h following the dose of vitamin C from subjects in a 'depleted' state and for 24 h from subjects in a 'supplemented' state and analysed for their vitamin C content. None of the pharmacokinetic parameters measured differed significantly between the two age groups. In contrast, the vast majority of these parameters were significantly different in depleted and supplemented subjects. The peak times (tmax) were greater in the depleted state in both young and elderly groups whereas the peak concentrations (Cmax) were greater in the supplemented state. The absorption rate constant (Ka) was significantly larger in the supplemented state compared to the depleted state in the young group and the absorption half-life (t 1/2, Ka) was significantly greater in the depleted state in the young group only. The absorption lag time (tlag) did not differ with respect to age or nutritional status. The elimination half-life (t 1/2, Ke) was significantly longer in supplemented subjects. Although the apparent high volume of distribution (Vd) was not significantly different within each age group the Vd was significantly greater in the depleted state when the two age groups were combined. The clearance (CL), and the nonrenal clearance (CLNR) were significantly greater in the depleted state. The renal clearance (CLR) and the amounts of vitamin C excreted in the 0- to 12- and 12- to 24-h intervals were significantly larger in the supplemented state. The urinary excretion data also indicate that, in supplemented subjects, an average of about 40 percent of the administered dose is excreted as unchanged vitamin C in the first 12 h after dosing, with very little being excreted thereafter.
The relations between vitamin status and immunological parameters or number of infections have been investigated in self-sufficient healthy individuals aged 60 and over. A total of 411 subjects agreed to participate, but 202 were discarded from the main statistical analysis since they could have had their immune or nutritional status modified by a recent infection, vaccination or drug consumption. Plasma concentrations of retinol, alpha-tocopherol, ascorbic acid and vitamin B6 were determined. Three indices of cellular immunity were measured: percentages of T-cell subsets, lymphoproliferative response to phytohaemaglutinin and delayed-type hypersensitivity to 7 ubiquitous antigens. A questionnaire about past infections was presented. Two results, supported by previous experimental observations, should be underlined. Vitamin B6 status was positively related to percentages of T-cell subsets: the lowest percentages of CD5 and CD4 cells were observed in the low B6 status group (50.6 and 32.6 per cent) and the highest percentages in the high B6 status group (62.0 and 41.0 per cent), with intermediate values in the medium group (57.6 and 39.5 per cent). Vitamin E status was negatively related to the number of past infections: subjects with a high alpha-tocopherol plasma concentration had fewer infections during the last 3 years (1.0) than those with a medium (2.2) or a low (2.3) concentration. In spite of these two observations, cellular immunity did not seem to be strongly related to vitamin status in the supposedly healthy population studied.
The levels of vitamin C in plasma, mononuclear (MN) and polymorphonuclear (PMN) leucocytes were measured in healthy, free-living, young and elderly women on three occasions over an 8-10-week period: (a) at entry into the study, (b) following 5 weeks of dietary depletion of vitamin C, and (c) following 3 weeks of supplementation with 500 mg of vitamin C per day. The combined mean vitamin C levels (expressed as microgram/10(8) cells) in MN cells were higher than those found in PMN cells at all three times, although the difference was only statistically significant in the depleted state. There were no age-related differences in the levels of vitamin C in plasma, MN or PMN cells at any of the three times. Significant overall differences in vitamin C levels between the entry and depleted and the depleted and supplemented states were observed for plasma and PMN cells but not for MN cells, possibly indicating that plasma and PMN cells are more sensitive indicators of vitamin C status than MN cells. The mean levels of vitamin C found in plasma clearly do 'track' those found in MN and PMN cells. However, attempted correlations between plasma and MN, plasma and PMN, and MN and PMN vitamin C levels at each time proved to be non-significant. In addition, the changes in vitamin C levels from entry to depleted and from depleted to supplemented times were non-significant when comparing plasma to MN and plasma to PMN, whereas the MN vs PMN comparison indicated a significant change in vitamin C levels between the depleted and supplemented states.(ABSTRACT TRUNCATED AT 250 WORDS)
This article has no abstract; the first 100 words appear below.
ASCORBIC acid, originally called vitamin C, is required for human health.¹ In human beings deprived of ascorbic acid, the deficiency disease scurvy develops and can be life threatening. Although a disease remarkably similar to scurvy was described by the ancient Egyptians,²,³ it was not until 1753 that a Scottish physician, James Lind, systematically described scurvy and its prevention by dietary means.⁴ Even then, the dietary requirements were controversial. For four decades the British navy refused to accept Lind's findings, and countless sailors continued to die unnecessarily from scurvy until lemon juice was finally included in sailors' rations. Research since Lind's . . .
I am indebted to David Blank for editorial assistance, to Gordon Cutler for encouragement, and to Shelley Sturman and Harvey Pollard in particular for helpful suggestions and consistent wholehearted support.
Source Information
From the Laboratory of Cell Biology and Genetics, National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md. Address reprint requests to Dr. Levine at Bldg. 4, Rm. 312, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892.
The changes in buffy layer (BL) vitamin C concentration following surgical operations were studied in relation to changes in the leucocyte and platelet counts. It was found that the postoperative fall and subsequent changes in BL vitamin C concentration corresponded to changes in the platelet/leucocyte ratio (PLR) in whole blood and consequently in the buffy layer preparations from which vitamin C concentrations were measured. The results of the study showed that the fall in BL vitamin C measured following operations is an artifact of the method used rather than a demand for vitamin C. It highlights the importance of measuring the PLR, and suggests the need for a differential leucocyte count, when undertaking BL vitamin C analysis.
Investigators at the Mayo Clinic conducted a placebo-controlled double-blind study in which 10 g of ascorbic acid was given to 150 patients with advanced cancer from a variety of primary sites. The results were clear-cut: Vitamin C was no better than placebo with respect to either amelioration of symptoms or survival time.
Aging is the progressive accumulation of changes with time that are associated with or responsible for the ever-increasing susceptibility to disease and death which accompanies advancing age. These time-related changes are attributed to the aging process. The nature of the aging process has been the subject of considerable speculation. Accumulating evidence now indicates that the sum of the deleterious free radical reactions going on continuously throughout the cells and tissues constitutes the aging process or is a major contributor to it. In mammalian systems the free radical reactions are largely those involving oxygen. Dietary manipulations expected to lower the rate of production of free radical reaction damage have been shown (i) to increase the life span of mice, rats, fruit flies, nematodes, and rotifers, as well as the "life span" of neurospora; (ii) to inhibit development of some forms of cancer; (iii) to enhance humoral and cell-mediated immune responses; and (iv) to slow development of amyloidosis and the autoimmune disorders of NZB and NZB/NZW mice. In addition, studies strongly suggest that free radical reactions play a significant role in the deterioration of the cardiovascular and central nervous systems with age. The free radical theory of aging provides reasonable explanations for age-associated phenomena, including (i) the relationship of the average life spans of mammalian species to their basal metabolic rates, (ii) the clustering of degenerative diseases in the terminal part of the life span, (iii) the beneficial effect of food restriction on life span, (iv) the greater longevity of females, and (v) the increase in autoimmune manifestations with age. It is not unreasonable to expect on the basis of present data that the healthy life span can be increased by 5-10 or more years by keeping body weight down, at a level compatible with a sense of well-being, while ingesting diets adequate in essential nutrients but designed to minimize random free radical reactions in the body.
Vitamin C and Cancer. New Engl
- R E Wittes
- L D Wright
Wittes, R.E.: Vitamin C and Cancer. New Engl. J. Med., 312-178-9, 1985. mins and Coenzymes, Vol. 62, edited by McCormick, D.B., and Wright, L.D., New York, Academic Press, 1979, pp. 3-11.
Complete Guide to Vitamins, Minerals, and Supplements
- H W Griffith
Nutrition Debate: Sorting Out Some Answers
- J D Gussow
- J.D. Gussow
- M.B. Davies
Incidence for premature rupture of membranes in pregnant women with low leukocyte levels of vitamin C
- M L Burr
- C J Bares
- G Godberg
- M.L. Burr
Comparison of plasma, mononuclear and polymorphonuclear leukocyte vitamin C levels in young and elderly women during depletion and supplementation
- J Blanchard
- K A Conrad
- R R Watson
- J. Blanchard