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LE Magazine August 2000
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Continued from Medical Abstracts, August 2000

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Selenium

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



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