Linus Pauling made Vitamin C famous by first claiming that C cured the common cold and later claimed that C might help reduce colon cancer. Pauling had an impact on scientific complacency and subsequent research into the basic biochemistry of Vitamin C and other antioxidant Vitamins has supported the notion that extra antioxidants may have benefits. Pauling's original claims have not been supported but other benefits of taking Vitamin C have become evident. Early US and Canadian RDAs suggested that 20 mg of Vitamin C per day would prevent scurvy; and, to leave a margin of error, 40 mg per day was recommended. Later, concerns that Vitamin C is destroyed by storage and cooking, and that food estimates of Vitamin C content may be misleading, lead to the increase in RDA to 60 mg per day. Pauling suggested important benefits from much higher doses, up to 15,000 mg per day. Others boldly treated cancer or AIDS patients with huge intravenous doses of Vitamin C, up to 100,000 mg per day! Now, we are far from the RDA and are reassured that even huge doses of Vitamin C are well tolerated. The range of actual use of Vitamin C is 60-100,000 mg/day! Whose advice are you going to follow?

The rational answer- finally, we have actual measurements to go by; one study that reveals the relationship of Vitamin C intake and the serum and tissue concentrations of Vitamin C is particularly helpful. We have accepted the conclusions as a guide for intake dose recommendations in the Alpha Nutrition Program. The optimal daily dose of Vitamin C is in a range of 200 to 400 mg per day.

Plasma and tissue concentrations of Vitamin C were determined at seven daily doses of Vitamin C from 30 to 2500 mg. Vitamin C Complete plasma saturation occurred at 1000 mg daily. Neutrophils, monocytes, and lymphocytes saturated at 100 mg daily and contained concentrations at least 14-fold higher than plasma. Bioavailability was complete for 200 mg of Vitamin C as a single dose. No Vitamin C was excreted in urine of six of seven volunteers until the 100-mg dose. At single doses of 500 mg and higher, bioavailability declined and the absorbed amount was excreted. Oxalate and urate excretion were elevated at 1000 mg of Vitamin C daily compared to lower doses. Based on these data and Institute of Medicine criteria, the current RDA of 60 mg daily should be increased to 200 mg daily, which can be obtained from fruits and vegetables. Safe doses of Vitamin C are less than 1000 mg daily, and Vitamin C daily doses above 400 mg have no evident value. (Proc Natl Acad Sci U S A, 93: 8, 1996 Apr 16, 3704-9 )

A human supplementation study was undertaken in order to investigate the correlation between the intake of individual daily dosages of Vitamin E (300 mg), Vitamin C (250 mg), or beta-carotene (15 mg) of eight week duration and their uptake in vivo in plasma and LDL. The effects of a combined supplement of Vitamin E, Vitamin C and beta-carotene (Redoxon protector-75 mg, 150 mg, 15 mg respectively) were also investigated. The results show that on supplementation with the individual antioxidants the increases in plasma alpha-tocopherol:cholesterol levels lie in the 1.5-2 fold range and the beta-carotene:cholesterol ratios give a mean 3.5 fold enhancement. The combined supplement containing the same level of beta-carotene as the single dosage achieved comparative levels of uptake in plasma. The level of plasma Vitamin C appears to be maximal at about 100 microM regardless of the pre-supplementation level. (Free Radic Res, 23: 5, 1995 Nov, 489-503 )

Functions and Benefits of Vitamin C

Protective effect of Vitamin C for non-hormone-dependent cancers of the esophagus, larynx, oral cavity, and pancreas, evidence for a protective effect of Vitamin C and/or other components in fruit is strong and consistent. For cancers of the stomach, rectum, breast, and cervix there is also evidence of protection. It is likely that ascorbic acid, carotenoids, and other factors in fruits and vegetables act jointly.

• Ascorbic acid regenerates metal ions in enzymes that require their required reduced forms.
• Protective effect from antioxidant Vitamins exists for ischemic heart disease and cataracts

Antioxidant Theory

One of the most persuasive arguments for the use of extra Vitamin C and other antioxidants is their ability to absorb free oxygen radicals. Cellular combustion can be compared to a stove, which needs adequate protection to do its job without burning the house down. As fuel burned in our cells, some oxygen atoms are given an extra electron and become the radical, O2-. Oxygen will also combine with hydrogen in the free hydroxyl radical -OH or in the highly reactive hydrogen peroxide molecule, H2O2. Tocopherols and tocotrienols (Vitamin E), ascorbic acid (Vitamin C), and the carotenoids react with these free radicals, notably peroxyl radicals, and with singlet molecular oxygen (O2 -). If O2- floats free of the energy engines, it may interact vigorously with other molecules. Cell membranes are vulnerable to O2- injury; damaged membranes disturb the function of the entire cell. Extra O2- reacting with DNA can make the code sticky and can cause mistakes in code reading or replication, resulting in cell mutation. The cumulative damage of trillions of random O2- encounters with critical molecules over many years contributes to accelerated aging and cellular dysfunction, like cancer. Cells contain oxygen detoxification enzymes: peroxidases, superoxide dismutase, and catalases. Several molecules combine harmlessly with O2- and are referred to as "antioxidants". Vitamin C is the cheapest, safest, and best antioxidant in town. If you can raise the amount of Vitamin C in cells, you may soak up enough O2- to make a long-term difference. The effect of Vitamin C is enhanced if you present two other nutrient antioxidants alongside, Vitamin E and selenium. You cannot take superoxide dismutase by mouth and expect benefit, since it will not arrive at the intracellular locations where it is needed.

Antioxidants in specific conditions:

The following articles summarize finding of benefit of antioxidants in a variety of conditions - complete references and abstracts of these articles are available in the associated course study material.

Osteoarthritis

Cumulative damage to tissues, mediated by reactive oxygen species, has been implicated as a pathway that leads to many of the degenerative changes associated with aging. An increased intake of antioxidant micronutrients might be associated with decreased rates of osteoarthritis (OA) in the knees, a common age-related disorder. Six hundred forty participants received complete assessments. Incident and progressive OA occurred in 81 and 68 knees, respectively. We found no significant association of incident OA with any nutrient. A 3-fold reduction in risk of OA progression was found for both the middle and highest Vitamin C intake. This related predominantly to a reduced risk of cartilage loss. Those with high Vitamin C intake also had a reduced risk of developing knee pain. A reduction in risk of OA progression was seen for beta carotene and Vitamin E intake CONCLUSION: High intake of antioxidant micronutrients, especially Vitamin C, may reduce the risk of cartilage loss and disease progression in people with OA.

Diabetes

J Am Coll Nutr, 14: 4, 1995 Aug, 387-92

The study investigated the metabolic benefits deriving from chronic pharmacological Vitamin C administration in aged non-insulin dependent (Type II) diabetic patients. Vitamin C (0.5 g twice daily) administration in double-blind, randomized, cross-over fashion. Treatment periods lasted 4 months Chronic Vitamin C administration vs placebo was associated with a significant decline in fasting plasma free radicals and insulin, LDL-cholesterol and triglycerides In 20 patients, chronic Vitamin C administration improved whole body glucose disposal and nonoxidative glucose metabolism. Percent increase in plasma Vitamin C levels correlated with the percent decline in plasma LDL-cholesterol and insulin levels. Chronic Vitamin C administration has beneficial effects upon glucose and lipid metabolism in aged non-insulin dependent (type II) diabetic patients.

J Clin Invest, 97: 1, 1996 Jan 1, 22-8

Endothelium-dependent vasodilation is impaired in humans with diabetes mellitus. Inactivation of endothelium-derived nitric oxide by oxygen-derived free radicals contributes to abnormal vascular reactivity in experimental models of diabetes. To determine whether this observation is relevant to humans, we tested the hypothesis that the antioxidant, Vitamin C, could improve endothelium-dependent vasodilation in forearm resistance vessels of patients with non-insulin-dependent diabetes mellitus. Forearm blood flow dose-response curves were determined for each drug before and during concomitant intraarterial administration of Vitamin C (24 mg/min).We conclude that endothelial dysfunction in forearm resistance vessels of patients with non-insulin-dependent diabetes mellitus can be improved by administration of the antioxidant, Vitamin C. These findings support the hypothesis that nitric oxide inactivation by oxygen-derived free radicals contributes to abnormal vascular reactivity in diabetes.

Diabetes Res Clin Pract, 28: 1, 1995 Apr, 1-8

In order to confirm the effect of ascorbic acid (AA) on human erythrocyte sorbitol accumulation and explore its mechanism of action, the effects of ascorbic acid in vitro on the sorbitol (S) and glucose (EG) content of human erythrocytes and in particular on the S/EG ratio as a marker of aldose reductase (AR) activity were carefully observed. The results showed that both the accumulation of erythrocyte sorbitol and the S/EG ratio were strongly reduced by the addition of AA. These results suggested that the polyol pathway could be inhibited effectively by AA through its direct action on AR. The results of a double-blind cross-over trial using AA tablets or inositol tablets in eight diabetic patients showed that the supplementation of 1000 mg AA/day for 2 weeks resulted in reductions of 12.2% and 21.8% in erythrocyte sorbitol and red cell sorbitol/plasma glucose (S/PG) ratio, respectively (P < 0.05), whereas the fasting plasma glucose levels measured coincidentally revealed no changes (P > 0.05).

Ann Nutr Metab, 39: 4, 1995, 217-23

The effect of magnesium (Mg) and ascorbic acid (AA) supplementation on metabolic control was assessed in 56 outpatient diabetics. A 90-day run-in period was followed by two 90-day treatment periods, during which Mg (600 mg/day) and AA (2 g/day) were administered in a randomized double-blind cross-over fashion. A decrease in systolic and diastolic blood pressure was observed in insulin-dependent diabetes mellitus subjects during Mg supplementation. No beneficial effect of Mg supplementation was observed on glycemic control, lipids or blood pressure in non-insulin-dependent diabetes mellitus (NIDDM) subjects. AA supplementation improved glycemic control among NIDDM subjects and both fasting blood glucose and HbA1c improved. Beneficial effects of AA supplementation on cholesterol and triglycerides were also observed in NIDDM subjects. The results suggest that high-dose AA supplementation may have a beneficial effect in NIDDM subjects on both glycemic control and blood lipids.

Atherosclerosis

Pharmacotherapy, 15: 5, 1995 Sep-Oct, 648-59

Hypercholesterolemia, cigarette smoking, hypertension, and obesity are known contributing risk factors for the development of atherosclerotic coronary artery disease (CAD). However, they account for only half of all cases of CAD, and the complete pathologic process underlying atherosclerosis remains unknown. Growing evidence suggests that oxidative modification of low-density lipoprotein (LDL) may be of particular importance in the pathogenesis. Oxidized LDL exhibits proatherogenic effects. Therefore, current research has focused on inhibiting the oxidation of LDL as a means of inhibiting the atherosclerotic process. One such approach is to enhance the endogenous antioxidant defense systems within the LDL particle with lipophilic antioxidants such as alpha-tocopherol and beta-carotene, or by supplementing the aqueous-phase antioxidant capacity with ascorbic acid. Observational data suggest a protective effect of antioxidant supplementation on the incidence of CAD; however, specific doses cannot be recommended since the data are inconclusive.

Am J Epidemiol, 142: 12, 1995 Dec 15, 1269-78

In the Western Electric Company Study, carried out in Chicago, Illinois, data on diet and other factors were obtained in 1958 and 1959 for a cohort of 1,556 employed, middle-aged men. Nutrients included Vitamin C and beta-carotene. An index that summarized combined intake of both nutrients was constructed. Mean intakes of Vitamin C in the lowest and highest tertiles of the index were 66 and 138 mg/day; corresponding values for beta-carotene were 2.3 and 5.3 mg/day. A total of 522 of 1,556 men died during 32,935 person-years of follow-up, 231 from coronary heart disease and 155 from cancer. These results support the hypothesis that consumption of foods rich in Vitamin C and beta-carotene reduces risk of death in middle-aged men.

J Am Diet Assoc, 95: 7, 1995 Jul, 775-80

To determine whether a fat- and energy-reduced diet rich in antioxidant Vitamins C and E, beta carotene, and soluble dietary fiber reduces free-radical stress and cardiac enzyme level and increases plasma ascorbic acid level 1 week after acute myocardial infarction. Subjects with definite or possible acute myocardial infarction and unstable angina (according to World Health Organization criteria) were assigned to either an intervention diet (n = 204) or a control diet (n = 202) within 48 hours of symptoms of infarction. INTERVENTIONS: Intervention and control groups were advised to consume a fat-reduced, oil-substituted diet. The intervention group was also advised to eat more fruits, vegetable soup, pulses, and crushed almonds and walnuts mixed with skim milk. : Consumption of an antioxidant-rich diet may reduce the plasma levels of lipid peroxide and cardiac enzyme and increase the plasma level of ascorbic acid. Antioxidant-rich foods may reduce myocardial necrosis and reperfusion injury induced by oxygen free radicals.

World J Surg, 19: 5, 1995 Sep-Oct, 738-44

The objective of this study was to evaluate the antioxidative properties of the multiVitamin cocktail Omnibionta (alpha-tocopherol, ascorbic acid, retinol, Vitamin B complex) in terms of diminishing lipid peroxidation with improvement of leg edema performance after limb revascularization operations in humans. Fifty-one subjects were selected; the control group contained 27 patients and the treatment group 24 patients, who received the Vitamin cocktail intravenously before the start of reperfusion. All patients suffered from acute or chronic arterial occlusive disease, except two subjects with arterial trauma. The results suggest that antioxidative Vitamin treatment might be valuable in preventing lipid peroxidation and decreasing extremity edema.

Can J Cardiol, 11 Suppl G:1995 Oct, 97G-103G

The oxidative modification of low density lipoprotein (LDL) may be an early step in atherogenesis. Furthermore, evidence of oxidized LDL has been found in vivo. The most persuasive evidence shows that supplementation of some animal models with antioxidants slows atherosclerosis. The purpose of this review is to examine the roles that Vitamin E, Vitamin C and beta-carotene may play in reducing LDL oxidation. Vitamin E has shown the most consistent effects with regard to LDL oxidation. Beta-carotene appears to have only a mild or no effect on oxidizability. Ascorbate, although it is not lipophilic, can also reduce LDL oxidative susceptibility.

Risk Of High Dose Antioxidants ?

Arch Intern Med, 156: 9, 1996 May 13, 925-35

As a result of the many scientific and popular press reports of the benefits of antioxidant Vitamins (Vitamin A, beta-carotene, Vitamin E, and ascorbic acid), it is estimated that 40% of the US population is consuming Vitamin supplements. The efficacy of these supplements is not yet proved, and some have questioned their safety. Approximately 10 to 15 cases of Vitamin A toxic reactions are reported per year in the United States, usually at doses greater than 100,000 IU/d. No adverse effects have been reported for beta-carotene. The frequency of Vitamin E toxic reactions is not well delineated, but case reports are few at dosages less than 3200 mg/d. Ascorbic acid toxic reactions are rare at dosages less than 4 g/d. Despite a lack of clinical trial data, it seems that antioxidant Vitamins are safe, although prudence might dictate their avoidance by women of childbearing potential, persons with liver disease or renal dysfunction, and those taking certain medications or undergoing specific laboratory tests.

J Urol, 155: 6, 1996 Jun, 1847-51

 

The association between the intake of Vitamins C and B6, and kidney stone formation was examined. We conducted a prospective study of the relationship between the intake of Vitamins C and B6 and the risk of symptomatic kidney stones in a cohort of 45,251 men 40 to 75 years old with no history of kidney calculi. Vitamin intake from foods and supplements was assessed using a semiquantitative food frequency questionnaire completed in 1986. RESULTS: During 6 years of followup 751 incident cases of kidney stones were documented. Neither Vitamin C nor Vitamin B6 intake was significantly associated with the risk of stone formation. : These data do not support an association between a high daily intake of Vitamin C or Vitamin B6 and the risk of stone formation, even when consumed in large doses.