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October 2002

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Serum micro nutrients and upper aerodigestive tract cancer.

Numerous dietary studies have found that vegetables and fruits protect against upper aerodigestive tract cancer. To evaluate the role of beta-carotene and other specific carotenoids, a nested case-control study using prediagnostic serum was conducted among 6832 American men of Japanese ancestry examined from 1971 to 1975. During a surveillance period of 20 years, the study identified 28 esophageal, 23 laryngeal and 16 oral-pharyngeal cancer cases in this cohort. The 69 cases were matched to 138 controls. A liquid chromatography technique, designed to optimize recovery and separation of the individual carotenoids, was used to measure serum levels of lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, beta-carotene, retinol, retinyl palmitate, and alpha-, delta-, and gamma tocopherol. With adjustment for cigarette smoking and alcohol intake, we found that alpha-carotene, beta-carotene, beta-cryptoxanthin, total carotenoids and gamma tocopherol levels were significantly lower in the 69 upper aerodigestive tract cancer patients than in their controls. Trends in risk by tertile of serum level were significant for these five micro nutrients. These significant trends persisted in cases diagnosed 10 or more years after phlebotomy for the three individual carotenoids and total carotenoid measurements. The odds ratios for the highest percentile were 0.19 (95% confidence interval, 0.05-0.75) for alpha-carotene, 0.10 (0.02-0.46) for beta-carotene, 0.25 (0.06-1.04) for beta-cryptoxanthin, and 0.22 (0.05-0.88) for total carotenoids. When the cases were separated into esophageal, laryngeal, and oral-pharyngeal cancer, both alpha-carotene and beta-carotene were consistently and strongly associated with reduced risk at each site. The findings suggest that alpha-carotene and other carotenoids, as well as beta-carotene, may be involved in the etiology of upper aerodigestive tract cancer.

Cancer Epidemiol Biomarkers Prev 1997 Jun;6(6):407-12

Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women.

BACKGROUND: The role of dietary antioxidant vitamins in preventing coronary heart disease has aroused considerable interest because of the knowledge that oxidative modification of low-density lipoprotein may promote atherosclerosis. METHODS. We studied 34,486 postmenopausal women with no cardiovascular disease who in early 1986 completed a questionnaire that assessed, among other factors, their intake of vitamins A, E and C from food sources and supplements. During approximately seven years of follow-up (ending December 31, 1992), 242 of the women died of coronary heart disease. RESULTS. In analyses adjusted for age and dietary energy intake, vitamin E consumption appeared to be inversely associated with the risk of death from coronary heart disease. This association was particularly striking in the subgroup of 21,809 women who did not consume vitamin supplements (relative risks from lowest to highest quintile of vitamin E intake, 1.0, 0.68, 0.71, 0.42 and 0.42; P for trend 0.008). After adjustment for possible confounding variables, this inverse association remained (relative risks from lowest to highest quintile, 1.0, 0.70, 0.76, 0.32 and 0.38; P for trend, 0.004). There was little evidence that the intake of vitamin E from supplements was associated with a decreased risk of death from coronary heart disease, but the effects of high-dose supplementation and the duration of supplement use could not be definitely addressed. Intake of vitamins A and C did not appear to be associated with the risk of death form coronary heart disease. CONCLUSIONS. These results suggest that in postmenopausal women the intake of vitamin E from food is inversely associated with the risk of death from coronary heart disease and that such women can lower their risk without using vitamin supplements. By contrast, the intake of vitamins A and C was not associated with lower risks of dying from coronary disease.

N Engl J Med 1996 May 2;334(18):1156-62

Differential effects of alpha and gamma tocopherol on low-density lipoprotein oxidation, superoxide activity, platelet aggregation and arterial thrombogenesis.

OBJECTIVES: This study was designed to examine the differential effects of alpha and gamma tocopherol on parameters of oxidation-antioxidation and thrombogenesis. BACKGROUND: Experimental studies have shown that antioxidants, such as vitamin E (alpha tocopherol), improve atherosclerotic plaque stability and vasomotor function, and decrease platelet aggregation and tendency to thrombus formation. METHODS: Sprague Dawley rats were fed chow mixed with alpha or gamma tocopherol (100 mg/kg/day) for 10 days. A filter soaked in 29% FeCl3 was applied around the abdominal aorta to study the patterns of arterial thrombosis. The aortic blood flow was observed and continuously recorded using an ultrasonic Doppler flow probe. ADP-induced platelet aggregation, low-density lipoprotein oxidation induced by phorbol 12-myristate 13-acetate (PMA)-stimulated leukocytes, superoxide anion generation and superoxide dismutase (SOD) activity were also measured. RESULTS: Both alpha and gamma tocopherol decreased platelet aggregation and delayed time to occlusive thrombus (all p < 0.05 vs. control). Both alpha and gamma tocopherol decreased arterial superoxide anion generation, lipid peroxidation and LDL oxidation (all p < 0.05 vs. control), and increased endogenous SOD activity (p < 0.05). The effects of gamma tocopherol were more potent than those of alpha tocopherol (p < 0.05). CONCLUSIONS: This study indicates that both alpha- and gamma tocopherol decrease platelet aggregation and delay intraarterial thrombus formation, perhaps by an increase in endogenous antioxidant activity. Alpha tocopherol is significantly more potent than alpha-tocopherol in these effects.

J Am Coll Cardiol 1999 Oct;34(4):1208-15

Optimal nutrition: vitamin E.

Interest in the role of vitamin E in disease prevention has encouraged the search for reliable indices of vitamin E status. Most studies in human subjects make use of static markers, usually alpha-tocopherol concentrations in plasma or serum. Plasma or serum alpha-tocopherol concentrations of < 11.6, 11.6-16.2, and > 16.2 mumol/l are normally regarded as indicating deficient, low and acceptable vitamin E status respectively, although more recently it has been suggested that the optimal plasma alpha-tocopherol concentration for protection against cardiovascular disease and cancer is > 30 mumol/l at common plasma lipid concentrations in combination with plasma vitamin C concentrations of > 50 mumol/l and > 0.4 mumol beta-carotene/l. Assessment of vitamin E status has also been based on alpha-tocopherol concentrations in erythrocytes, lymphocytes, platelets, lipoproteins, adipose tissue, buccal mucosal cells and LDL, and on alpha-tocopherol: gamma-tocopherol in serum or plasma. Erythrocyte susceptibility to haemolysis or lipid oxidation, breath hydrocarbon exhalation, oxidative resistance of LDL, and alpha-tocopheryl quinone concentrations in cerebrospinal fluid have been used as functional markers of vitamin E status. However, many of these tests tend to be non-specific and poorly standardized. The recognition that vitamin E has important roles in platelet, vascular and immune function in addition to its antioxidant properties may lead to the identification of more specific biomarkers of vitamin E status.

Proc Nutr Soc 1999 May;58(2):459-68

Gamma-tocopherol decreases ox-LDL-mediated activation of nuclear factor-kappaB and apoptosis in human coronary artery endothelial cells.

Gamma-tocopherol, produced by many plants, is the major form of tocopherol in the United States diet. It is an effecient protector of lipids against peroxidative damage. Epidemiologic studies show that supplementation of diet with gamma-tocopherol is inversely related to the risk of death from cardiovascular disease. This study was conducted to examine the role of gamma-tocopherol in oxidized LDL (ox-LDL)-induced nuclear factor (NF)-kappaB activation and apoptosis in human coronary artery endothelial cells (HCAECs). Cultured HCAECs were treated with ox-LDL (10-40 microgram/ml). Incubation of HCAECs with ox-LDL resulted in apoptosis of HCAECs, as determined by TUNEL and DNA laddering. Ox-LDL degraded IkappaB protein and activated NF-kappaB in HCAECs (both P < 0.01 vs control), as determined by Western blot. Treatment of cells with gamma-tocopherol attenuated ox-LDL-mediated degradation of IkappaB and activation of NF-kappaB (both P < 0.01 vs ox-LDL alone). The presence of gamma-tocopherol also reduced ox-LDL-induced apoptosis (P < 0.01 vs ox-LDL alone). A high concentration of gamma-tocopherol (50 micromol/L) was more effective than the low concentration of gamma-tocopherol (10 micromol/L) in this process. These observations show that ox-LDL induces apoptosis of HCAECs at least partially by activation of NF-kappaB signal transduction pathway. Gamma-tocopherol significantly decreases ox-LDL-induced apoptosis of HCAECs by inhibiting the activation of NF-kappaB.

Biochem Biophys Res Commun 1999 May 27;259(1):157-61

Vitamin E deficiency in variant angina.

BACKGROUND: Oxidative modification of LDL has been suggested to increase coronary vasoreactivity to agonists. A deficiency of vitamin E, a major antioxidant, may be related to the occurrence of coronary artery spasm. METHODS AND RESULTS: Vitamin E levels were determined with the use of high-performance liquid chromatography in normolipidemic subjects, including 29 patients with active variant angina (group 1), 13 patients with inactive stage of variant angina without anginal attacks during the past 6 months (group 2), 32 patients with a significant (>75%) organic coronary stenosis and stable effort angina (group 3), and 30 patients without coronary artery disease (group 4). Total lipid levels in blood were calculated as total cholesterol plus triglyceride levels. The plasma alpha-tocopherol levels as well as alpha-tocopherol/lipids were significantly lower in group 1 than in groups 2 through 4. Also, the plasma gamma-tocopherol levels were significantly lower in group 1 than in groups 2 through 4. The vitamin E levels were not significantly different between group 1 patients with and those without a significant organic stenosis. In group 1, both alpha- and gamma-tocopherol levels were significantly elevated after a > or = six-month angina-free period. The alpha-tocopherol levels in the LDL fraction were significantly lower in group 1 than in group 4. Plasma alpha-tocopherol levels were significantly correlated with those in the LDL fractions. In six patients of group 1 still having anginal attacks while receiving calcium channel blockers, the addition of vitamin E acetate (300 mg/d) significantly elevated plasma alpha-tocopherol levels and inhibited the occurrence of angina. CONCLUSIONS: Plasma vitamin E levels were significantly lower in patients with active variant angina than in subjects without coronary spasm, suggesting an association between vitamin E deficiency and coronary artery spasm.

Circulation 1996 Jul 1;94(1):14-8

Gamma-tocopherol: an efficient protector of lipids against nitric oxide-initiated peroxidative damage.

Nitric oxide released by macrophages during inflammation reacts with active oxygen to form peroxynitrite. Peroxynitrite nitrates protein and peroxidizes lipids. Gamma-tocopherol traps peroxynitrite and is more effective than alpha-tocopherol in protecting lipids against such peroxidation.

Nutr Rev 1997 ct;55(10):376-8

Gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: physiological implications.

Peroxynitrite, a powerful mutagenic oxidant and nitrating species, is formed by the near diffusion-limited reaction of .NO and O2.- during activation of phagocytes. Chronic inflammation induced by phagocytes is a major contributor to cancer and other degenerative diseases. We examined how gamma-tocopherol (gammaT), the principal form of vitamin E in the United States diet, and alpha-tocopherol (alphaT), the major form in supplements, protect against peroxynitrite-induced lipid oxidation. Lipid hydroperoxide formation in liposomes (but not isolated low-density lipoprotein) exposed to peroxynitrite or the .NO and O2.- generator SIN-1 (3-morpholinosydnonimine) was inhibited more effectively by gammaT than alphaT. More importantly, nitration of gammaT at the nucleophilic 5-position, which proceeded in both liposomes and human low density lipoprotein at yields of approximately 50% and approximately 75%, respectively, was not affected by the presence of alphaT. These results suggest that despite alphaT’s action as an antioxidant gammaT is required to effectively remove the peroxynitrite-derived nitrating species. We postulate that gammaT acts in vivo as a trap for membrane-soluble electrophilic nitrogen oxides and other electrophilic mutagens, forming stable carbon-centered adducts through the nucleophilic 5-position, which is blocked in alphaT. Because large doses of dietary alphaT displace gammaT in plasma and other tissues, the current wisdom of vitamin E supplementation with primarily alphaT should be reconsidered.

Proc Natl Acad Sci U S A 1997 Apr 1;94(7):3217-22

Effect of alpha- and gamma-tocopherol as well as cholesterol on lipid peroxidation.

For a period of 15 weeks growing rats were fed low fat diets containing equimolar doses of alpha- and gamma-tocopherol (180 and 174 ppm) as well as mixtures of alpha- and gamma-tocopherol (3:1; 1:1; 1:3) without cholesterol or with 1% cholesterol. The influence of these supplements on lipid peroxidation and tocopherol retention in the liver were investigated. The tocopherol status was estimated by measuring the activities of creatine kinase and transaminases (GOT, GPT) in plasma as well as by in vitro hemolysis of erythrocytes. The in vitro hemolysis rate was only lowered by alpha-tocopherol and the mixtures of alpha- and gamma-tocopherol. In response to lipid peroxidation in the liver, alpha-tocopherol was the more efficient antioxidant, whereas gamma-tocopherol was more efficient in the diet. Cholesterol had a lowering effect on lipid peroxidation in vitro and in vivo; cholesterol in combination with alpha-tocopherol had a stabilizing effect on the erythrocyte membrane. Moreover, there was a positive effect of cholesterol on tocopherol retention in the liver. The biological activity of gamma-tocopherol in relation to alpha-tocopherol was calculated according to the test criterium; it ranged from 22% to 100%.

Z Ernahrungswiss 1986 Mar;25(1):47-62

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