Life Extension Magazine®

Issue: Aug 2000

Vitamin E, Vitamin C, Selenium, Carotene, more

Scientifically reviewed by: Dr. Gary Gonzalez, MD, on January 2021.


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Vitamin E

Chronic vitamin E administration improves brachial reactivity and increases intracellular magnesium concentration in type II diabetic patients

Vascular disease accounts for the majority of the clinical complications in diabetes mellitus. As an exaggerated oxidative stress degree has been postulated as the link between diabetes mellitus and endothelial function, a possible positive effect of plasma vitamin E (Vit.E) administration on brachial reactivity could be postulated. Our study aims at investigating the possible effect of chronic Vit.E administration on brachial reactivity, oxidative stress indexes, and intracellular magnesium and calcium content in type II diabetic patients free of diabetic complications. Forty adult, type II diabetic patients were enrolled in the study, which was deigned as a double blind, randomized vs. placebo trial. At baseline all patients underwent the following tests: I) anthropometric and metabolic examinations, 2) evaluation of oxidative stress indexes, 3) intracellular magnesium and calcium measurements, and 4) determination of arterial compliance and distensibility .Then, all patients were randomly assigned to Vit.E treatment at a dose of 600 mg/day (Evion Forte; n = 20) or placebo (n = 20) over 8 weeks. At the end of this treatment period, a complete reevaluation of the patients was made. Vit.E treatment was associated with a significant improvement in the percent change in brachial artery diameter (P<0.03) and oxidative stress indexes (P< 0.005). In the Vit.E group, the percent change in brachial artery diameter correlated positively with the percent change in oxidative stress indexes ( oxidized/reduced glutathione, TrolQx-equivalent antioxidant capacity, thiobarbituric acid reaction products, lipid peroxides) and intracellular cation content (magnesium and calcium). After adjustment for age, sex, body mass index, and wait/hip ratio, all of these correlations remained significant (P<O.O3 for all). Furthermore, adjusting for glycosylated hemoglobin, plasma total cholesterol, and homeostatic model index, brachial artery diameter was still correlated with the percent change in oxidative stress indexes (P<O.O4 for all). Nevertheless, the relationship between the percent change in brachial artery diameter and oxidative stress indexes was no longer significant after adjustment for intracellular Mg and Ca2+. In conclusion, our study demonstrates that chronic administration of Vit.E improves brachial artery reactivity in patients with type II diabetes mellitus. Such an effect seems mediated by a reduction in oxidative stress and a regulation of intracellular calcium and magnesium contents.

J Clin Endocrinol Metab 2000 Jan,'85(1):109-15

Reversal of defective nerve conduction with vitamin E supplementation in type 2 diabetes: a preliminary study

OBJECTIVE: The present study has examined the effect of vitamin E, the principal modulator of free radical activity , on electrophysiological parameters in patients with diabetic peripheral sensorimotor polyneuropathy, matched for duration of disease and metabolic control. RESEARCH DESIGN AND METHDS: A total of 21 subjects with type 2 diabetes were enrolled in this double-blind randomized placebo-controlled study (vitamin E, 11 patients; placebo, 10 patients). Patients were randomly assigned to receive either 900 mg vitamin E or placebo for 6 months. The average dietary vitamin E consumption of the subjects was similar during the study. The main outcome measure was the electrophysiological tests assessing nerve conduction. Fasting plasma glucose, HbA1, postprandial plasma glucose, and electro- physiological parameters in the basal state and after 6 months of treatment were studied. RESULTS: Glycemic indexes did not show any significant changes during the study, whereas nerve conduction improved significantly in 2 of the 12 studied electrophysiological parameters after 6 months in patients on vitamin E supplementation. The changes in the electrophysiological parameters were obvious in the median motor nerve fibers and tibial motor nerve fibers. Nerve conduction velocity in the median motor nerve fibers (P = 0.0019) and tibial motor nerve distal latency (P = 0.0284) improved significantly after 6 months of vitamin E supplementation.

CONCLUSIONS: This study shows that defective nerve conduction in diabetic subjects with mild-to-moderate peripheral neuropathy may be improved by pharmacological doses of vitamin E supplementation. Further studies with a larger number of patients for longer periods of time are needed.

Diabetes Care 1998 Nov; 21(11):1915-8

Reducing lipid peroxidation stress of erythrocyte membrane by alpha-tocopherol nicotinate plays an important role in improving blood rheological properties in type 2 diabetic patients with retinopathy

The effects of alpha-tocopherol nicotinate on blood viscoelasticity and viscosity and on lipid peroxidation stress in erythrocyte membranes in patients with Type 2 DM were investigated. Thirteen Type 2 diabetic subjects with retinopathy were given alpha-tocopherol nicotinate 300 mg tds, after meals, for 3 months. The treatment resulted in significant reductions of blood viscosity at different shear rates (e.g. -2.23 2.82 p<0.015, gamma = 1.5 s(-l)) and viscoelasticity (p<0.004); resistance of erythrocyte deformation (p<0.001) and lipid peroxidation stress in red cell membrane (malondialdehyde or MDA reduced by 0.17 0.13 nmoll(-l) p<0.005). Plasma viscosity, red cell rigidity, and HbA1c were unchanged. There were negative linear correlations between the indices of red cell deformability and the levels of MDA of red cell membrane both pre- and post-treatment ( e.g. R = -0.79, p<0.001; R = -0.78, p<0.002, n = 13; pre- and post-, respectively). We suggest that the improvements of rheolagical properties of blood and red cell deformability by alpha-tocopherol nicotinate are mainly attributed to reducing lipid peroxidation stress on membrane of red blood cells. The treatment may be useful in slowing deterioration of micro angiopathy in Type 2 DM.

Debate Bed 1998 May;15(5):380-5

Vitamin E and Immunity

OBJECTIVE: To determine whether long-term supplementation with vitamin E enhances in via, clinically relevant measures of cell-mediated immunity in healthy elderly subjects. DESIGN: Randomized, double-blind, placebo- controlled intervention study. SETTING AND PARTICIPANTS: A total of 88 free-living, healthy subjects at least 65 years of age. INTERVENTION: Subjects were randomly assigned to a placebo group or to groups consuming 60, 200, or 800 mg/d of vitamin E for 235 days. MAIN OUT - COME MEASURES: Delayed-type hypersensitivity skin response (DTH); antibody response to hepatitis B, tetanus and diphtheria, and pneumococcal vaccines; and autoantibodies to DNA and thyroglobulin were assessed before and after supplementation. RESULTS: Supplementation with vitamin E for 4 months improved certain clinically relevant indexes of cell-mediated immunity in healthy elderly. Subjects consuming 200 mg/d of vitamin E had a 65% increase in DTH and a 6-fold increase in antibody titer to hepatitis B compared with placebo (17% and 3-fold, respectively), 60-mg/d (41 % and 3-fold, respectively), and 800-mg/d (49% and 2.5- fold, respectively) groups. The 200-mg/d group also had a significant increase in antibody titer to tetanus vaccine. Subjects in the upper tertile of serum alpha-tocopherol (vitamin E) concentration (>48.4 micromol/L [2.08 mg/dL]) after supplementation had higher antibody response to hepatitis B and DTH. Vitamin E supplementation had no effect on antibody titer to diphtheria and did not affect immunoglobulin levels or levels of T and B cells. No significant effect of vitamin E supplementation on autoantibody levels was observed. CONCLUSIONS: Our results indicate that a level of vitamin E greater than currently recommended enhances certain clinically relevant in vivo indexes of T -cell-mediated function in healthy elderly persons. No adverse effects were observed with vitamin E supplementation.

JAMA (1997 May 7) 277(17):1380-6

Vitamins E plus C and interacting conutrients required for optimal health. A critical and constructive review of epidemiology and supplementation data regarding cardiovascular disease and cancer

Antioxidants are crucial components of fruit/vegetable rich diets preventing cardiovascular disease ( CVD ) and cancer: plasma vitamins C, E, carotenoids from diet correlate prevalence of CVD and cancer inversely, low levels predict an increased risk of individuals which is potentiated by combined inadequacy ( e.g., vitamins C + E, C + carotene, A + carotene ); self -prescribed rectification of vitamins C and E at adequacy of other micronutrients reduce forthcoming CVD, of vitamins A, C, E, carotene and conutrients also cancer; randomized exclusive supplementation of beta-carotene + 1- vitamin A or E lack benefits except prostate cancer reduction by vitamin E, and overall cancer reduction by selenium; randomized intervention with synchronous rectification of vitamins A + C + E + B + minerals reduces CVD and counteracts pre- cancerous lesions; high vitamin E supplements reveal potentials in secondary CVD prevention. Plasma values desirable for primary prevention: > or = 30 mumol/llipid- standardized vitamin E ( alpha-tocopherol/cholesterol > or = 5.0 mumol/mmol); > or = 50 mumol/l vitamin C aiming at vitamin C/vitamin E ratio > 1.3-1.5; > or = 0.4 mumol/l beta- (> or = 0.5 mumol/l alpha+ beta-) carotene.

CONCLUSIONS: In CVD vitamin E acts as first risk discriminator, vitamin C as second one; optimal health requires synchronously optimized vitamins C + E, A, carotenoids and vegetable conutrients.

Biofactors 1998;7(1-2);113-74

Therapeutic uses of vitamin E in prevention of atherosclerosis

The purpose of this review is to present the evidence- based pharmacotherapeutic properties of vitamin E and provide clinical recommendations for use in the arena of atherosclerosis. Methods: A literature search was conducted from 1966 through March 1999. All usable papers were retrieved, with large, randomized, double-blinded, clinical trials and epidemiological trials receiving emphasis.

Results: Vitamin E, a lipid soluble vitamin, is a potent antioxidant. Several epidemiological studies have demonstrated positive relationships between vitamin E intake and the prevention of atherosclerotic heart disease; however, only one, large randomized clinical trial (The CHAOS Trial) has been conducted using more than 400 IU per day of vitamin E. Positive outcomes included a 77- percent reduction in nonfatal myocardial infarction (MI), but no corresponding reduction in mortality. Several large clinical trials are ongoing, investigating vitamin E for the prevention of atherosclerosis. Much less work has been undertaken studying vitamin E for prevention of cerebro- and peripheral vascular disease, but there appears to be promise in these areas as well.

Conclusions: On the basis of the literature search, the authors recommend 400 ill or more per day of vitamin E to patients at high risk or already diagnosed with coronary artery disease. Vitamin E supplementation may also be beneficial in the prevention of cerebro- and peripheral vascular diseases.

Altern Med Rev 1999 Dec;4(6);414-23

Cost-effectiveness of vitamin E therapy in the treatment of patients with angiographically proven coronary narrowing (CHAOS trial) - Cambridge Heart Antioxidant Study

Epidemiologic studies have suggested that vitamin E (alpha-tocopherol) may playa preventive role in reducing the incidence of atherosclerosis. The aim of this paper was to conduct a cost- effectiveness analysis of vitamin E supplementation in patients with coronary artery disease using data from the Cambridge Heart Antioxidant Study (CHAOS). The study compared cost-effectiveness in the context of Australian and United States (US) health care utilization. The main clinical outcome used in the economic evaluation was the incidence of acute myocardial infarction (AMI) which was nonfatal. Utilization of health care resources was estimated by conducting a survey of Australian clinicians and published Australian and US cost data. Cost savings of $127 (A$181) and $578/patient randomized to vitamin E therapy compared with patients receiving placebo were found for Australian and US settings, respectively. Savings in the vitamin E group were due primarily to reduction in hospital admissions for AMI. This occurred because the vitamin E group had a 4.4% lower absolute risk of AMI than did the placebo group. Less than 10% of health care costs in the Australian evaluation was due to vitamin E ($150 (A$214/patient]). Our economic evaluation indicates that vitamin E therapy in patients with angiographically proven atherosclerosis is cost-effective in the Australian and US settings.

Am J Cardiol 1998 Aug 15;82(4):414-7

Neurologic findings in vitamin E deficiency

Vitamin E is one of the most important lipid-soluble antioxidant nutrients. Severe vitamin E deficiency can have a profound effect on the central nervous system. Cystic fibrosis, chronic cholestatic liver disease, abetalipoproteinemia, short bowel syndrome, isolated vitamin E deficiency syndrome and other malabsorption syndromes all may cause varying degrees of neurologic deficits due to related vitamin deficiencies. The classic abnormalities in vitamin E deficiency progress from hyporeflexia, ataxia, limitations in upward gaze and strabismus to long-tract defects, profound muscle weakness and visual field constriction. Patients with severe, pro- longed deficiency may develop complete blindness, dementia and cardiac arrhythmias. Treatment must be tailored to the underlying cause of vitamin E deficiency and may include oral or parenteral vitamin supplementation. The more advanced the deficits, the more limited the response to therapy. Therefore, a good neurologic examination and periodic serum vitamin E levels are essential in patients at risk of vitamin E deficiency.

Am Pam Physician 1997 Jan;55(1):197-201

Partners in defense, vitamin E and vitamin C

In addition to the enzymic mechanism of free-radical removal, essential nutrients that can scavenge free radicals, such as vitamins E and C, constitute a strong line of defense in retarding free radical induced cellular damage. Distinct pathways for the repair of oxidized vitamin E in human cells have been recently identified. Within 0.5 min after the addition of arachidonic acid to a human platelet homogenate, over half of the platelet vitamin E and added arachidonate were metabolized by platelet cyclooxygenase and lipoxygenase pathways. After adding nordihydroguaiaretic acid, a lipoxygenase inhibitor and a strong reductant, over 60% of the oxidized vitamin E was regenerated. To test other physiological, water-soluble reductants that may help regenerate vitamin E, eicosatetraynoic acid, a lipoxygenase inhibitor that is not an antioxidant, was used. In this system, both ascorbate and glutathione provided significant vitamin E regeneration. Kinetic analysis and studies of vitamin E regeneration in a protein-denaturing system revealed that ascorbate regenerates vitamin E by a nonenzymic mechanism, whereas glutathione regenerates vitamin E enzymatically. These studies suggest that significant interaction occurs between water- and lipid-soluble molecules at the membrane-cytosol interface and that vitamin C may function in vivo to repair the membrane-bound oxidized vitamin E.

Can J Physiol Pharmacol 1993 Sep;71 (9):725-31


Vitamin C

Scurvy-a mistakenly forgotten disease

Four cases of scurvy diagnosed within a period of two years are reported. They comprised 2 male patients with heavy nicotine and alcohol abuse, a 35-year-old woman with malnutrition due to food supplements phobia, and a 69-year-old woman with malnutrition due to dementia and social isolation. All four patients were adynamic and anemic. Three patients showed typical dermatologic signs with hemorrhagic hyperceratosis, suffusions or cork-screw hair. Two patients complained of parodontol disorders. Other symptoms were gastrointestinal bleeding, sicca syndrome, retinal bleeding, subdural hematoma, edema and arthralgia. Associated disorders were folic acid and vita- min B12 depletion in two cases, and nephropathy and pneumonia with pneumothorax in one case each. In all cases the serum ascorbic acid concentration was below the scorbutic level of 11 mumol/l. Historical data, pathogenesis, incidence, clinical presentation, diagnosis and therapy of scurvy are discussed. We conclude that scurvy can be observed even in a developed country such as Switzerland at the end of the 20th century. The real incidence may be underestimated because symptoms are not well known and disappear rapidly after admission because of sufficient vitamin C content in normal diet. Patients at risk are socially isolated alcoholics, old people, psychiatric patients and diet enthusiasts. Usually scurvy occurs in con- junction with other deficiencies. Smoking and acute illness enhance ascorbic acid depletion. With a knowledge of the symptomatology of scurvy, it is easy to diagnose and treatment is simple and effective.

Schweiz Med Wochenschr 1994 Aug 9;124(31-32):1373-80

Enhancement of natural killer cell activity and T and B cell function by buffered vitamin C in patients exposed to toxic chemicals: the role of protein kinase

After exposure to many toxic chemicals, NK function can be decreased significantly. Weeks or months later, natural killer (NK) function can rebound to normal levels in some and can be suppressed for prolonged periods of time in other patients. In view of this, we decided to study the effect of buffered vitamin C on NK, T and B cell function in patients who had been exposed to toxic chemicals. After the first blood draw, 55 patients immediately ingested granulated buffered vitamin C in water at a dosage of 60 mg/Kg body weight. Exactly 24 hours later, blood was again drawn for a follow-up study of NK, T and B cell function. Vitamin C in high oral dose was capable of enhancing NK activity up to ten-fold in 78% of patients. Lymphocyte blastogenic responses to T and B cell mitogens were restored to the normal level after vitamin C usage. Signal transduction enzyme protein kinase C (PKC) appeared to be involved in the mechanism of induction of NK activity by vitamin C. We conclude that immune functional abnormalities can be restored after toxic chemical exposure by oral usage of vitamin C.

Immunopharmacol lmmunotoxicol 1997 Aug;19(3);291-312

Serum carotene, vitamin A, and vitamin C levels in breast cancer and cancer of the uterine cervix

Levels of carotene, vitamin A, and vitamin C measured in the serum of patients with cancer of the breast and uterine cervix were compared with levels in healthy controls and patients with benign diseases of the breast and cervix. Serum ascorbate levels were significantly lower in patients with benign diseases of the breast and cervix than in controls. In cancer patients, there was a significant . trend of lower serum vitamin levels with increasing stage of the disease.

Nutr Cancer 1996;25(2);173-7

Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer

Ascorbic acid metabolism is associated with a number of mechanisms known to be involved in host resistance to malignant disease. Cancer patients are significantly depleted of ascorbic acid, and in our opinion this demonstrable biochemical characteristic indicates a substantially increased requirement and utilization of this substance to potentiate these various host resistance factors. The results of a clinical trial are presented in which 100 terminal cancer patients were given supplemental ascorbate as part of their routine management. Their progress is compared to that of 1000 similar patients treated identically, but who received no supplemental ascorbate. The mean survival time is more than 4.2 times as great for the ascorbate subjects (mote than 210 days) as for the controls (50 days). Analysis of the survival-time curves indicates that deaths occur for about 90% of the ascorbate-treated patients at one-third the rate for the controls and that the other 10% have a much greater survival time, averaging more than 20 times that for the controls. The results clearly indicate that this simple and safe form of medication is of definite value in the treatment of patients with advanced cancer.

Proc Natl Acad Sci USA 1976 Oct;73(10);3685-9

Vitamin C and oral health

Maintaining natural dentition is a realistic goal given today's improved caries control and attention to good oral hygiene. Expanding knowledge in the area of periodontal diseases provides further insight into health pro- motion practices which can be effective in preventing tooth loss. Vitamin C's role in maintaining the health of teeth and gingivae remains unchallenged. Now clinical evidence indicates that vitamin C functions in improving host defense mechanisms and is thereby implicated in preserving periodontal health. Common sense tells us that the monitoring of the vitamin C status of individuals, especially those at high risk ( e.g., diabetics, smokers, elderly, etc.) for inadequate intakes, will yield positive results for periodontal health. Patient education pro- grams that stress the importance of good nutrition, while at the same time providing practical information for the selection of a well balanced diet, are simple measures that will benefit many.

J Can Dent Assoc 1989 Sep,55(9);705-7

Effects of high doses of vitamins C and E against doxorubicin-induced chromosomal damage in Wistar rat bone marrow cells

Doxorubicin (DXR) is one of the major antitumoral agents available for clinical use. In addition to intercalating into the DNA molecule, this drug generates free radicals. Vitamins C (VC) and E (YE) can protect normal cells from the damage caused by radicals without interfering with the cytotoxicity of DXR against tumors. The objective of the present study was to investigate the possible protective effect of VC and/or YE on mammalian cells treated with DXR in vivo. Animals treated with the lowest doses of VC and/or YE, alone or in combination, plus a single dose of DXR presented a statistically significant reduction in total number of chromosome aberrations and in number of abnormal metaphases. The highest vitamin doses tested caused no changes in the parameters analyzed when compared with control. Under the present experimental conditions, the efficiency of VC and/or YE in protecting against chromosome damage was dependent on the dose used.

Mutat Res 1998 Nov 9;419(1-3):137-43

Ascorbic acid may protect against human gastric cancer by scavenging mucosal oxygen radicals

High dietary ascorbic acid intake appears to protect against gastric cancer. This may be due to its action as a scavenger of reactive radical species formed in the gastric mucosa, resulting in a reduced level of radical-mediated DNA damage. We have studied 82 patients, of whom 37 had Helicobacter pylori-associated gastritis, a condition which predisposes to gastric cancer. Using electron paramagnetic resonance (EPR) spectroscopy we have demonstrated, for the first time, that ascorbyl radicals are generated in human gastric mucosa, presumably as a result of scavenging of free radicals by ascorbic acid Quantification of ascorbyl radicals demonstrates that there is a higher concentration in those patients with H.pylori gastritis compared with subjects with normal his- tology (P < 0.01). We also found gastric mucosalluminol-enhanced chemiluminescence and malondialdehyde concentrations (which are believed to be markers of radical generation and tissue damage) to be higher in patients with H.pylori gastritis compared with those with normal histology (P < 0.001 and P < 0.01 respectively). The observed concentrations of the ascorbyl radical correlate with the level of luminol-enhanced chemiluminescence (r = 0.41, P < 0.001 ), but not with malondialdehyde concentrations (r = 0.08, P = 0.47). Mucosal ascorbic acid and total vitamin C concentrations did not vary between histological groups, nor did they correlate with mucosal levels of the ascorbyl radical, chemiluminescence or malondialdehyde. These data suggest that ascorbic acid is acting as a scavenger of free radicals generated in human gastric mucosa. The experiments therefore provide direct supportive evidence for the hypothesis that ascorbic acid protects against gastric cancer by scavenging reactive radical species which would otherwise react with DNA, with resultant genetic damage.

Carcinogenesis 1996 Mar;17(3):559-62

Interaction of ascorbate and alpha-tocopherol

Vitamins C and E function as water-soluble and lipid- soluble chain-breaking antioxidants, respectively, and protect lipids, proteins, and membranes from oxidative damage. Vitamin C scavenges oxygen radicals in the aqueous phase, whereas vitamin E scavenges oxygen radicals within the membranes. Vitamin C regenerates vitamin E by reducing vitamin E radicals formed when vitamin E scavenges the oxygen radicals. This interaction between vitamin C and vitamin E radicals can take place not only in homogeneous solutions but also in liposomal membrane systems where vitamins C and E reside separately outside and within the membranes respectively, and vitamin C can act as a synergist.

Ann N Y Acad Sci 1987;498:186-99

Vitamin C improves endothelial function of epicardial coronary arteries in patients with hypercholesterolaemia or essential hypertension--assessed by cold pressor testing

AIMS: There is evidence that formation of free radicals increases in patients with hypertension or hypercholesterolaemia, which may contribute to endothelial dysfunction of epicardial coronary arteries due to inactivation of the vasodilator NO. The present study was designed to test whether the abnormal constriction of epicardial coronary arteries due to sympathetic stimulation by the cold pressor test in patients with essential hypertension or hypercholesterolaemia could be reversed by administration of the antioxidant vitamin C. METHODS and RESULTS: In 28 patients without relevant coronary artery stenosis the cold pressor test was performed before and after a 3 g infusion of vitamin C. In five normal controls the cold pressor test led to a similar increase in lumi- nal area before and after vitamin C (3.7+/-1.3% and 1.9+/-0.8%, ns vs before vitamin C). In nine hypercholesterolaemic patients the cold pressor test led to a -14.1 +/- 2.8% reduction in cross-sectional area before vitamin C. This constriction was significantly improved after vitamin C to -7.6%+/-2.0, P=0.027 Vs before vitamin C. In nine hypertensive patients, the cold pressor test led to a 17.1+/-3.2% decrease in cross-sectional area before vitamin C, which was improved to -7.1 + /-3.1 after vitamin C, P=O.OO4 Vs before vitamin C. This increase in luminal area was significant in each group in comparison with normal controls (each P<O.O5). Administration of saline (placebo group, five patients) had no significant effect on cold pressor test-induced constriction ( -6.9+/-3.9% before and -6. 8+/-3.7% after saline). CONCLUSION: The antioxidant vitamin C reverses cold pressor test- induced vasoconstriction of epicardial coronary arteries in patients with hypertension or hypercholesterolaemia. Our data suggest that enhanced oxidative stress contributes to impaired endothelial function in this patient population.

Eur Heart J 1999 Nov;20(22):1676-80


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Selenium and cardiovascular pathology

Selenium deficiency has established implications in cardiovascular diseases, particularly on cardiac muscle integrity. The essential trace element takes part not only in the direct protection of endothelial cells against the accumulation of aggressive oxygen species, but also in the biosynthesis of arachidonic acid derivatives involved in platelet and leucocyte functions, or in the regulation of cholesterol. Moreover, it prevents toxic effects of cadmium and mercury , and modulates the active transport of calcium. Some clinical investigations have underlined its importance in the cardiac function and the prevention of coronary atherosclerosis, and several recent prospective epidemiological studies have attributed to selenium deficiency a greater incidence of cardiovascular diseases. Further studies should be devoted to the influence of marginal deficiency in this trace element whose optimal requirement does not seem to be met by the usual dietary intake.

Bur Heart J 1999 Nov;20(22):1676-80

Selenium: physiologic role and value in human pathology

Abstract: Selenium (Se) is a metalloid with chemical properties closed to those of sulfur, but they can not substitute for one another in vivo. Se body content reflected soil Se content (13 to 20 mg in North Americans, 3 to 6 in New Zealand residents). The daily intake recommended is 50 to 200 micrograms. In the diet Se occurs in mineral or organic forms, the bioavailability of these latter is better. Se as selenocysteine is incorporated in specific proteins such as glutathione peroxidase (GSH-Px). Se is metabolized in H2Se by reductive pathways. H2Se is methylated and methylated compounds are excreted in the urines. The Se urinary excretion represents the principal known process of Se regulation. Se bound to GSH- Px participates to free radical destruction and cellular membrane protection. Its role is complementary of vita- min E effect. Se also seems indispensable to appropriate immune response. It can chelate various metals allowing their detoxication. Se metabolism can be studied by Se assay in serum, whole blood, urine (reference values must be performed for each studied population) and by GSH- Px activity determination in erythrocytes or platelets. Vitamin E assay completes estimation of the antioxidative status of organism. Few Se intoxications have been recognized but Se deficiencies often happen. They can lead to a cardiomyopathy (Keshan disease ), increase the risk of cardiovascular diseases or cancer. Se deficiencies are found in chronic renal failure, malnutrition malabsorption, long term parenteral nutrition. At the present time it is not known how Se deficiency interfers with chronic infections which often go with these diseases. A better knowledge of Se requirements and Se role could allow an appropriate supplementation in various diseases.

Pathol Biol (Paris), 1988 Oct, 36;8, 1017-25

Serum selenium and the risk of coronary heart disease and stroke

The association between serum selenium concentration and five-year risk of cardiovascular disease was studied in 1,110 men aged 55 to 74 years in two rural areas of Finland. In the total cohort, all-cause and cardiovascular deaths were associated significantly with serum selenium of less than 45 micrograms/liter, an adjusted relative risk of 1.4 (95% confidence interval (Cl), 1.0-2.0, p less than 0.05) and 1.6 (95% CL, 1.1-2.3, p less than 0.05), respectively. Among men free of coronary heart disease at the outset, these associations were of similar magnitude but did not attain statistical significance. Among men free of stroke at the outset, low serum selenium was associated significantly with stroke mortality, an adjusted relative risk of 3.7 (95% CL, 1.0-13.1). The associations of coronary deaths and myocardial infarctions with low serum selenium were nonsignificant.

Source Am J Epidemiol, 1985 Aug, 122:2, 276-82

Selenium: geochemical distribution and associations with human heart and cancer death rates and longevity in China and the United States

The geochemistry of available soil Se varies enormously in different localities, and the corresponding amounts moving up through crops to food vary accordingly. In a belt extending from northeastern to south central China, the available soil Se was measured by human blood Se levels. Severe deficiency occurred at 8-26 ng/mL; subadequate amounts occurred in large areas with 32-83 ng/ml; adequate amounts of 200-300 ng/ml occurred in large cities; and toxic amounts of 3000- 7800 ng/ml occurred in terrace areas where runoff from the uplands evaporated, and in certain other soils. Some heart deaths (Keshan Disease) occurred in children 1 to 10 yr of age in the most deficient areas, but were prevented by 230-900 micro- grams/wk Se supplementation. One mg Se/wk was the adult dosage. In Se deficient areas, the life span of adults was lowered severely (35 to 45 yr), with heart muscle dam- age common at autopsy. Se and Zn deficiencies are apparently associated with stomach cancer. The geochemistry of Se in the USA is also highly variable, blood Se ranging from 100-350 ng/ml Se data for individuals are limited; however, ischemic heart death correlated inversely with blood Se in 25 cities of 22 states ( r = -.70; p less than .01 ). Counties of Wisconsin and Florida are highly variable in human heart death and cancer death rates, as are the 50 states, suggesting Se geographic variability.

Biol Trace Elem Res, 1988 Jan, 15:, 13-21

Selenium deficiency in HIV infection and the acquired immunodeficiency syndrome (AIDS)

Selenium is required for activity of the enzyme glutathione peroxidase, and selenium deficiency may be associated with myopathy, cardiomyopathy and immune dysfunction including oral candidiasis, impaired phagocytic function and decreased CD4 T -cells. We assessed selenium status in 12 patients with AIDS compared to normals and found significantly low plasma and red blood cell levels. Plasma selenium in AIDS was 0.043 +1- 0.01 micro- gram/mi vs 0.095 +1- 0.016 in controls (P < 0.001). Selenium status correlated with serum albumin (r = 0.77; P < 0.001) and 60% had documented GI malabsorption as determined by abnormal D-Xylose tests. In a subsequent study blood selenium and glutathione peroxidase were diminished in 12 AIDS and 8 ARC patients compared with normals (all P < 0.001). For glutathione peroxidase the mean levels were decreased by 45% in AIDS and 27% in ARC versus controls (P < 0.001 ). Both plasma selenium and glutathione peroxidase significantly correlated with total lymphocyte counts (r = 0.65; P < 0.001; glutathione peroxidase and lymphocyte counts). This occurred in both homosexuals and drug users with AIDS and irrespective of the presence or absence of diarrhea or GI malabsorption. To determine if tissue levels of selenium were also depleted we studied cardiac selenium levels in autopsy AIDS hearts compared to age and sex matched controls. Cardiac selenium in AIDS was 0.327 +1- 0.082 micrograms/g dry weight versus 0.534 +1- 0.184 in controls (P < 0.01). Two cases had histologic cardiomyopathy pathologically consistent with the cardiomyopathy described in Keshan disease associated with low selenium blood levels. To further assess mechanisms of nutrient and selenium deficiency in AIDS we studied dietary intake in outpatients and inpatients with various stages of HIV infection. Inadequate selenium intake based on a computer (Nutritionist 3) analysis of 72 h diet records was present in only 17% of clinically stable HIV positive outpatients and 71% of inpatients with AIDS. Conclusions: Selenium deficiency is common in HIV positive patients as documented by low plasma and red blood cell levels of selenium, diminished activity of glutathione peroxidase, and low cardiac selenium levels in AIDS hearts. Patients with AIDS tend to have more severe deficits than those with earlier stages of HIV infection. The selenium deficit in blood does correlate with serum albumin levels and total lymphocyte counts. Poor dietary intake and malabsorption could lead to this condition which has important implications for both cardiac and immune functions in HIV positive patients.

Chem Biol Interact, 1994 Jun, 91:2-3, 181-6

Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong

High rates of hepatitis B virus (HBV) infection and primary liver cancer (PLC) are present in Qidong county. Epidemiological surveys demonstrated an inverse association between selenium (Se) level and regional cancer incidence, as well as HBV infection. Four-year animal studies showed that dietary supplement of Se reduced the HBV infection by 77.2% and liver precancerous lesion by 75.8% of ducks, caused by exposure to natural environmental etiologic factors. An intervention trial was undertaken among the general population of 130,471. Individuals in five town- ships were involved for observation of the preventive effect of Se. The 8-yr follow-up data showed reduced PLC incidence by 35.1% in selenized table salt supplemented vs the nonsupplemented population. On withdrawal of Se from the treated group, PLC incidence rate began to increase. However, the inhibitory response to HBV was sustained during the 3-yr cessation of treatment. The clinical study among 226 Hepatitis B Surface Antigen (HBsAg)-positive persons provided either 200 micrograms of Se in the form of selenized yeast tablet or an identical placebo of yeast tablet daily for 4 yr showed that 7 of 113 subjects were diagnosed as having PLC in the placebo group, whereas no incidence of PLC was found in 113 subjects supplemented with Se. Again on cessation of treatment, PLC developed at a rate comparable to that in the control group, demonstrating that a continuous intake of Se is essential to sustain the chemopreventive effect.

Biol Trace Elem Res 1997 Jan;56(1):117-24

High dose antioxidant supplementation to MS patients - effects on glutathione peroxidase, clinical safety, and absorption of selenium

High-dose antioxidant supplementation has recently been recommended for multiple sclerosis (MS) patients. This study tests the clinical safety, the glutathioneperoxidase (GSH-px) activity, and the absorption of selenium during such supplementation. Eighteen MS patients were given 6 tablets especially made for this study, equivalent to 6 mg sodium selenite, 2 g VITAMIN C, and 480 mg vita- min E a day for five wk. GSH-px, which was lower than in non-MS controls before the start of treatment, increased fivefold during 5 wk of treatment. Side effects were scarce. Ten MS patients were subjected to a 24-h selenium absorption study after ingestion of 2 active tablets, equivalent to 2 mg sodium selenite. Selenium, which was low initially, increased 24% during the first 3 h and then stabilized. It is concluded that the tested antioxidant treatment seems to be safe and that MS patients have low GSH-px, which may be increased by the tested antioxidant treatment.

Biol Trace Elem Res 1990 Feb;24(2):109-17

Hepatitis C virus encodes a selenium-dependent glutathione peroxidase gene. Implications for oxidative stress as a risk factor in progression to hepatocellular carcinoma

Using structural bioinformatics methods, the aim is to assess the hypothesis that hepatitis C virus (HCV) encodes a glutathione peroxidase (GPx) gene in an over- lapping reading frame, linking HCV expression and pathogenesis to the Se status and dietary oxidant/Antioxidant balance of the host. METHODS: The putative HCV GPx gene was identified by searching viral sequence databases, using conserved GPx active site sequences as probes, giving particular weight to the UGA (selenocysteine) codon. Multiple sequence alignments were generated and analyzed to validate the sequence similarity, and to establish the degree of conservation of the identified genomic features in HCV: Molecular modeling was used to assess the structural feasibility of the proposed homology. RESULTS: The GPx homology region overlaps the NS4 gene, and is well conserved in HCV: The sequence similarity of the conserved active site regions to a set of known GPx is high ( 4 to 6 SD greater than expected for similar random sequences). The computed strain energy of a molecular model of the HCV GPx is energetically favorable, comparable to the bovine GPx structure. CONCLUSIONS: By linking HCV replication and pathogenesis to the Se status and dietary oxidant/antioxidant balance of the host, the existence of a viral GPxgene could help to explain why HCV disease progression is accelerated by oxidant stresses such as alcoholism and iron overload.

Source Med Klin, 1999 Oct, 94 SuppI 3:, 2-6


Carotene and other Caronteoids

Beta-carotene enhances the recovery of lymphocytes from oxidative DNA damage

Epidemiological studies have revealed a strong correlation between high intake of fruit and vegetables and low incidence of certain cancers. Micronutrients present in these foods are thought to decrease free radical attack on DNA and hence protect against mutations that cause cancer, but the fine details of the causal mechanism have still to be elucidated. Whether dietary factors can modulate DNA repair--a crucial element in the avoidance of carcinogenesis--is an intriguing question that has not yet been satisfactorily answered. In order to investigate the effects of beta-carotene on oxidative damage and its repair, volunteers were given a single 45 mgdose and lymphocytes taken before and after the supplement were treated in vitro with H202. DNA strand breaks and oxidised pyrimidines were measured at intervals, to monitor the removal of oxidative DNA damage. We found inter-individual variations in response. In cases where the baseline plasma beta-carotene concentration was high, or where supplementation increased the plasma concentration, recovery from oxidative damage (i.e. removal of both oxidised pyrimidines and strand breaks ) was relatively rapid. However, what seems to be an enhancement of repair might in fact represent an amelioration of the continuing oxidative stress encountered by the lymphocytes under in vitro culture conditions. We found that culture in a 5% oxygen atmosphere enhanced recovery of lymphocytes from H202 damage.

Acta Biochim Pol 1998;45(1):183-90

The effect of a low carotenoid diet on malondialdehyde- thiobarbituric acid (MDA-TBA) concentrations in women: a placebo-controlled double-blind study

OBJECTIVE: The purpose of the study was to evaluate the effect of a low carotenoid diet (83 micrograms Beta- carotene) on malondialdehyde-thiobarbituric acid (MDA-TBA) concentrations of nine pre-menopausal women. METHODS: Subjects lived on the metabolic research unit of the Western Human Nutrition Research Center (WHNRC), where diet, exercise and other activities were controlled. Five subjects (Group C, control group) consumed a low carotenoid diet and received an additional 0.5 fig/day of Beta-carotene while four subjects (Group P, placebo group) received only the low carotenoid diet during days 1 to 60 (period 1 ). All subjects received 0.5 fig/day of Beta-carotene during days 60 to 100 (period 2), plus three capsules/day mixed carotenoid supplement (Neo-Life Company) during study days 100 to 120. Changes in MDA-TBA concentrations were analyzed during the study periods and between the groups. RESULTS: At the start of the study ( day 1 ), no significant difference in the MDA-TBA concentration was observed between the control (Group C) and the placebo (Group P) subjects. During period 1 (days 2 to 60), when Group p subjects consumed the low carotenoid diet without supplementation, the MDA- TBA values for Group p rose markedly and were significantly (p < 0.05) higher than the MDA-TBA values for Group C subjects who were receiving carotenoid supplementation. During period 2 (days 60 to 100) when both groups received carotenoid supplementation, the MDA- TBA values of Group p subjects were significantly (p < 0.05) reduced to the point where they were similar to the MDA-TBA values for Group C subjects. CONCLUSIONS: These findings provide evidence to support the beneficial effects of carotenoidsin preventing lipid peroxidation in the cells. Further studies are needed to identify the exact mechanism by which carotenoids prevent lipid peroxidation and the amount needed for normal activity.

J Am Call Nutr 1998 Feb;17(1),54-8

Does tomato consumption effectively increase the resistance of lymphocyte DNA to oxidative damage ?

BACKGROUND: Lycopene, the main carotenoid in tomato, has been shown to be a potent antioxidant in vitro. However, there is no significant evidence of its antioxidant action in vivo. OBJECTIVE: We evaluated the effect of tomato intake on plasma carotenoid concentrations and lymphocyte resistance to oxidative stress. DESIGN: Ten healthy women ( divided into 2 groups of 5 subjects each) ate a diet containing tomato puree (providing 16.5 fig lycopene) and a tomato-free diet for 21 d each in a crossover design. Before and after each diet period, plasma carotenoid concentrations and primary lymphocyte resistance to oxidative stress ( evaluated by means of single-cell gel electrophoresis) were analyzed. RESULTS: After the first 21-d experimental period, total plasma lycopene concentrations increased by 0.5 micromol/L (95% CI: 0.14,0.87) in the group that consumed the tomato diet and decreased by 0.2 micromol/L (95% CI: - 0.11, -0.30) in the group that consumed the tomato-free diet (P < 0.001 ). Tomato consumption also had an effect on cellular antioxidant capacity: lymphocyte DNA damage after ex vivo treatment with hydrogen peroxide decreased by 33% (95% CI: 0.8%, 61 %; P < 0.05) and by 42% (95% CI: 5.1 %, 78%; P < 0.05) in the 2 groups of subjects after consumption of the tomato diet. CONCLUSION: The consumption of tomato products may reduce the susceptibility of lymphocyte DNA to oxidative damage.

Am J Clin Nutr 1999 Apr;69(4):712-8

Concentrations of carotenoids, tocopherols, and retinol in paired plasma and cervical tissue of patients with cervical cancel, precancel, and noncancerous diseases

Paired blood (collected after an overnight fast) and cervical tissue (cancerous, precancerous, and noncancerous) samples were obtained from 87 patients (age, 21-86 years) who had a hysterectomy or biopsy due to cervical cancer, precancer ( cervical intraepithelial neoplasia I, II, and III), or noncancerous diseases. The samples were analyzed using high-performance liquid chromatography for 10 micronutrients (lutein, zeaxanthin, beta-ctyptoxanthin, lycopene, alpha-carotene, beta-carotene, cis-beta-carotene, alpha- tocopherol, gamma-tocopherol, and retinol). The results indicated that: ( a) among the three patient groups, the mean plasma concentrations of all micronutrients except gamma-tocopherol were lowest in the cancer patients; how- ever, the mean tissue concentrations of the two tocopherols and certain carotenoids were highest in the cancerous tissue; and (b) among the 10 micronutrients, only the concentrations of beta-carotene and cis-beta-carotene were lower in both the plasma and tissue of cancer and precancer patients than in those of noncancer controls. These results suggest that: ( a) not all of the micronutrient concentrations in plasma reflect the micronutrient concentrations in cervical tissue; thus, in some cases, it may be necessary to measure the tissue micronutrient concentrations to define the role of the micronutrients in cervical carcinogenesis; and (b) maintaining an adequate plasma and tissue concentration of beta-carotene may be necessary for the prevention of cervical cancer and precancer.

Cancer Epidemiol Biomarkers Prev 1998 Apr;7(4):347-50

Effects of carotenoids on human immune function

Many epidemiological studies have shown an association between diets rich in carotenoids and a reduced incidence of many forms of cancer, and it has been suggested that the antioxidant properties of these compounds are a causative factor. Attention has focused on the potential role of one specific carotenoid, beta-carotene, in preventing cancer, and numerous publications have described in vitro experiments and animal studies which suggest that not only can this carotenoid protect against the development of cancer, but also several other chronic diseases. Since the immune system plays a major role in cancer prevention, it has been suggested that beta-carotene may enhance immune cell function. Several human trials, using dietary beta-carotene supplementation with a wide range of intakes, have been undertaken to address this hypothesis. The general conclusion of these studies is that this compound can enhance cell-mediated immune responses, particularly in the elderly. The present article will review some of these human studies and, hopefully, complement the reviews of other authors associated with the present symposium, some of whom will also describe work in this area. Potential mechanisms for the effects of carotenoids on immune function will also be reviewed. Finally, possible reasons for the failure of three major prospective studies to demonstrate a beneficial effect of beta-carotene supplementation on lung cancer risk will be discussed.

Proc Nutr Soc 1999 Aug;58(3):713-8

Effects of long-term oral beta-carotene supplementation on lipid peroxidation in patients with cystic fibrosis

The aim of this study was to determine the efficacy of oral beta-carotene supplementation for the correction of an oxidant-antioxidant imbalance in cystic fibrosis (CF). We studied 24-patients with cystic fibrosis and 14 healthy controls. 13 CF-patients were allocated to a CF-supplementation group, which received 1 mg beta-carotene/kg BW Id up to a body weight (BW) of 50 kg, patients with a BW greater 50 kg received 50 mg beta-caroteneld for 12 weeks. For the following 12 weeks an patients of the CF-supplementation group were treated with 10 mg beta-caroteneld. Placebos with starch were applied to 11 CF-patients. Baseline plasma beta-carotene concentrations of CF patients (mean +1- SD, 0.08 +1- 0.04 mumol/l) were significantly lower than those of age-matched controls (0.3 +1- 0.1 mumol/l) (p < 0.001). beta-carotene concentrations of the CF-supplementation group increased rapidly and reached a value of 0.6 mumol/l after 12 weeks of supplementation. Normal values were measured for plasma ascorbate and alpha-tocopherol. Plasma retinol concentrations were in the lower normal range and did not increase during supplementation. Total antioxidative capacity in plasma of the CF-supplementation group increased after 12 weeks of supplementation at an extent of 12%. Positive influence was indicated by a decrease of plasma malondialdehyde. Thus oral beta- carotene supplementation is effective in normalizing status of beta-carotene and malondialdehyde in CF patients.

Int J Vitam Nutr Res 1998;68(2):83-7

A prospective study of carotenoid intake and risk of cataract extraction in US men

BACKGROUND: Dietary antioxidants, including carotenoids, are hypothesized to decrease the risk of age- related cataracts by preventing oxidation of proteins or lipids within the lens. However, prospective epidemiologic data concerning this phenomenon are limited. OBJECTIVE: Our objective was to examine prospectively the association between carotenoid and vitamin A intakes and cataract extraction in men. DESIGN: US male health professionals (n = 36644) who were 45-75 y of age in 1986 were included in this prospective cohort study. Others were subsequently included as they became 45 y of age. A detailed dietary questionnaire was used to assess intake of carotenoids and other nutrients. During 8 y of follow-up, 840 cases of senile cataract extraction were documented. RESULTS: We observed a modestly lower risk of cataract extraction in men with higher intakes of lutein and zeaxanthin but not of other carotenoids ( alpha-carotene, beta- carotene, lycopene, and beta-cryptoxanthin) or vitamin A after other potential risk factors, including age and smoking, were controlled for. Men in the highest fifth of lutein and zeaxanthin intake had a 19% lower risk of cataract relative to men in the lowest fifth (relative risk: 0.81; 95% CI: 0.65, 1.01; p for trend = 0.03). Among specific foods high in carotenoids, broccoli and spinach were most consistently associated with a lower risk of cataract. CONCLUSIONS: Lutein and zeaxanthin may decrease the risk of cataracts severe enough to require extraction, although this relation appears modest in magnitude. The present findings add support for recommendations to consume vegetables and fruit high in carotenoids daily.

Am J Clin Nutr 1999 Oct;70(4);517-24

The anti-carcinogenic role of Iycopene, abundantly present in tomato

Among the many carotenoids present in nature, lycopene has been of special interest and has received attention in recent times due to its suggestive association in reducing risk for cancer at many sites including breast, prostate and pancreas. Several studies have attempted to determine the bioactive levels of this carotenoid in human tissues and the influence of plant food and cancer on carotenoid levels. Experimental studies have also implicated the protective role of lycopene during carcinogenesis. These observations should justify further exploration and evaluation of the biological function of lycopene alone or in combination with other chemical compounds present in tomato fruit for their use in cancer prevention.

Eur J Cancer Prev 1999 Aug;8(4):325-30

Inhibitory effects of carotenoids on the invasion of rat ascites hepatoma cells in culture

The effects of carotenoids-alpha-carotene, beta- carotene, lycopene, beta-cryptoxanthin, zeaxanthin, lutein, canthaxanthin, astaxanthin-on the invasion of rat ascites hepatoma AH109A cells were investigated by co-culturing the hepatoma cells with rat mesentery-derived mesothelial cells (M-cells). All the carotenoids examined inhibited AH109A invasion in a dose-dependent manner up to 5 microM. Cancer cells previously cultured with hypoxanthine (HX) and xanthine oxidase (XO) showed a highly invasive activity. Carotenoids, 5 microM of beta-carotene and astaxanthin, suppressed this reactive oxygen species- potentiated invasive capacity by simultaneously treating AH109A cells with the carotenoids, HX and XO. These results suggest that the antioxidative property of these carotenoids may be involved in their anti-invasive action.

Cancer Lett 2000 Apr 3;151(1);111-5