Vitamin E Abstracts 3

© 2013

Does gamma-tocopherol play a role in the primary prevention of heart disease and cancer? A review

         (Dietrich, Traber et al. 2006) Download

Vitamin E consists of a group of eight isomers, four tocopherols (alpha-, beta-, gamma-, delta-tocopherol) and four tocotrienols (alpha-, beta-, gamma-, delta-tocotrienol). While extensive literature has been published on the potential health benefits of alpha-tocopherol, little is known about gamma-tocopherol, the major form of vitamin E in food in the U.S. gamma-tocopherol has recently received more research attention based on findings from in vitro and animal studies indicating that it has potent anti-inflammatory and antioxidant properties. Based on these recent studies, it is important to investigate the possible health benefits of gamma-tocopherol in humans. In this article, we review publications on dietary gamma-tocopherol intake, plasma gamma-tocopherol levels, cardiovascular disease and cancer risk in humans.

New perspectives on vitamin E: gamma-tocopherol and carboxyelthylhydroxychroman metabolites in biology and medicine

         (Hensley, Benaksas et al. 2004) Download

Vitamin E (alpha-tocopherol or alphaT) has long been recognized as a classic free radical scavenging antioxidant whose deficiency impairs mammalian fertility. In actuality, alpha-tocopherol is one member of a class of phytochemicals that are distinguished by varying methylation of a chroman head group. Early studies conducted between 1922 and 1950 indicated that alpha-tocopherol was specific among the tocopherols in allowing fertility of laboratory animals. The unique vitamin action of alphaT, combined with its prevalence in the human body and the similar efficiency of tocopherols as chain-breaking antioxidants, led biologists to almost completely discount the "minor" tocopherols as topics for basic and clinical research. Recent discoveries have forced a serious reconsideration of this conventional wisdom. New and unexpected biological activities have been reported for the desmethyl tocopherols, such as gamma-tocopherol, and for specific tocopherol metabolites, most notably the carboxyethyl-hydroxychroman (CEHC) products. The activities of these other tocopherols do not map directly to their chemical antioxidant behavior but rather reflect anti-inflammatory, antineoplastic, and natriuretic functions possibly mediated through specific binding interactions. Moreover, a nascent body of epidemiological data suggests that gamma-tocopherol is a better negative risk factor for certain types of cancer and myocardial infarction than is a alpha-tocopherol. The potential public health implications are immense, given the extreme popularity of alphaT supplementation which can unintentionally deplete the body of gamma-tocopherol. These findings may or may not signal a major paradigm shift in free radical biology and medicine. The data argue for thorough experimental and epidemiological reappraisal of desmethyl tocopherols, especially within the contexts of cardiovascular disease and cancer biology.

gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells

         (Jiang, Elson-Schwab et al. 2000) Download

Cyclooxygenase-2 (COX-2)-catalyzed synthesis of prostaglandin E(2) (PGE(2)) plays a key role in inflammation and its associated diseases, such as cancer and vascular heart disease. Here we report that gamma-tocopherol (gammaT) reduced PGE(2) synthesis in both lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and IL-1beta-treated A549 human epithelial cells with an apparent IC(50) of 7.5 and 4 microM, respectively. The major metabolite of dietary gammaT, 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC), also exhibited an inhibitory effect, with an IC(50) of approximately 30 microM in these cells. In contrast, alpha-tocopherol at 50 microM slightly reduced (25%) PGE(2) formation in macrophages, but had no effect in epithelial cells. The inhibitory effects of gammaT and gamma-CEHC stemmed from their inhibition of COX-2 activity, rather than affecting protein expression or substrate availability, and appeared to be independent of antioxidant activity. gamma-CEHC also inhibited PGE(2) synthesis when exposed for 1 h to COX-2-preinduced cells followed by the addition of arachidonic acid (AA), whereas under similar conditions, gammaT required an 8- to 24-h incubation period to cause the inhibition. The inhibitory potency of gammaT and gamma-CEHC was diminished by an increase in AA concentration, suggesting that they might compete with AA at the active site of COX-2. We also observed a moderate reduction of nitrite accumulation and suppression of inducible nitric oxide synthase expression by gammaT in lipopolysaccharide-treated macrophages. These findings indicate that gammaT and its major metabolite possess anti-inflammatory activity and that gammaT at physiological concentrations may be important in human disease prevention.

Gamma-tocopherol supplementation inhibits protein nitration and ascorbate oxidation in rats with inflammation

         (Jiang, Lykkesfeldt et al. 2002) Download

Gamma-tocopherol (gammaT) complements alpha-tocopherol (alphaT) by trapping reactive nitrogen oxides to form a stable adduct, 5-nitro-gammaT [Christen et al., PNAS 94:3217-3222; 1997]. This observation led to the current investigation in which we studied the effects of gammaT supplementation on plasma and tissue vitamin C, vitamin E, and protein nitration before and after zymosan-induced acute peritonitis. Male Fischer 344 rats were fed for 4 weeks with either a normal chow diet with basal 32 mg alphaT/kg, or the same diet supplemented with approximately 90 mg d-gammaT/kg. Supplementation resulted in significantly higher levels of gammaT in plasma, liver, and kidney of control animals without affecting alphaT, total alphaT+gammaT or vitamin C. Intraperitoneal injection of zymosan caused a marked increase in 3-nitrotyrosine and a profound decline in vitamin C in all tissues examined. Supplementation with gammaT significantly inhibited protein nitration and ascorbate oxidation in the kidney, as indicated by the 29% and 56% reduction of kidney 3-nitrotyrosine and dehydroascorbate, respectively. Supplementation significantly attenuated inflammation-induced loss of vitamin C in the plasma (38%) and kidney (20%). Zymosan-treated animals had significantly higher plasma and tissue gammaT than nontreated pair-fed controls, and the elevation of gammaT was strongly accentuated by the supplementation. In contrast, alphaT did not significantly change in response to zymosan treatment. In untreated control animals, gammaT supplementation lowered basal levels of 3-nitrotyrosine in the kidney and buffered the starvation-induced changes in vitamin C in all tissues examined. Our study provides the first in vivo evidence that in rats with high basal amounts of alphaT, a moderate gammaT supplementation attenuates inflammation-mediated damage, and spares vitamin C during starvation-induced stress without affecting alphaT.


Failure of vitamin E in clinical trials: is gamma-tocopherol the answer?

         (Jialal and Devaraj 2005) Download

Oxidative stress and inflammation play a crucial role in atherosclerosis. However, prospective clinical trials of dietary antioxidants with anti-inflammatory properties, such as alpha-tocopherol (AT), have not yielded positive results. AT supplementation decreases gamma-tocopherol (GT) levels. GT is an antioxidant with potent anti-inflammatory activity, and plasma GT levels are inversely associated with cardiovascular diseases. Thus, studies using pure GT, alone or in conjunction with AT, will elucidate its utility in cardiovascular disease prevention.

Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-gamma

            (Lee, Ju et al. 2009) Download

PURPOSE: Tocopherols are lipophilic antioxidants present in vegetable oils. Although the antioxidant and anticancer activities of alpha-tocopherol (vitamin E) have been studied for decades, recent intervention studies with alpha-tocopherol have been negative for protection from cancer in humans. The tocopherols consist of four isoforms, which are the alpha, beta, gamma, and delta variants, and recent attention is being given to other isoforms. In the present study, we investigated the inhibitory effect of a tocopherol mixture rich in gamma- and delta-tocopherols against mammary tumorigenesis. EXPERIMENTAL DESIGN: Female Sprague Dawley rats were treated with N-methyl-N-nitrosourea (NMU), and then fed diets containing 0.1%, 0.3%, or 0.5% mixed tocopherols rich in gamma- and delta-tocopherols for 9 weeks. Tumor burden and multiplicity were determined, and the levels of markers of inflammation, proliferation, and apoptosis were evaluated in the serum and in mammary tumors. The regulation of nuclear receptor signaling by tocopherols was studied in mammary tumors and in breast cancer cells. RESULTS: Dietary administration of 0.1%, 0.3%, or 0.5% mixed tocopherols suppressed mammary tumor growth by 38%, 50%, or 80%, respectively. Tumor multiplicity was also significantly reduced in all three mixed tocopherol groups. Mixed tocopherols increased the expression of p21, p27, caspase-3, and peroxisome proliferator activated receptor-gamma, and inhibited AKT and estrogen signaling in mammary tumors. Our mechanistic study found that gamma- and delta-tocopherols, but not alpha-tocopherol, activated peroxisome proliferator activated receptor-gamma and antagonized estrogen action in breast cancer. CONCLUSION: The results suggest that gamma- and delta-tocopherols may be effective agents for the prevention of breast cancer.

Supplementation of a gamma-tocopherol-rich mixture of tocopherols in healthy men protects against vascular endothelial dysfunction induced by postprandial hyperglycemia

         (Mah, Noh et al. 2013) Download

Postprandial hyperglycemia induces oxidative stress responses, impairs vascular endothelial function (VEF) and increases the risk of cardiovascular disease. We hypothesized that the antioxidant and anti-inflammatory activities of a gamma-tocopherol-rich mixture of tocopherols (gamma-TmT) would protect against vascular dysfunction that is otherwise caused by postprandial hyperglycemia by decreasing oxidative stress and proinflammatory responses, and improving nitric oxide (NO*) homeostasis. In a randomized, crossover study, healthy men (n=15; 21.8 +/- 0.8 years) completed a fasting oral glucose challenge (75 g) with or without prior supplementation of gamma-TmT (5 days). Brachial artery flow-mediated dilation (FMD), plasma glucose, insulin, antioxidants, malondialdehyde (MDA), inflammatory proteins, arginine and asymmetric dimethylarginine (ADMA) were measured at regular intervals during a 3-h postprandial period. Supplementation of gamma-TmT increased (P<.05) plasma gamma-T by threefold and gamma-carboxyethyl-hydroxychroman by more than ninefold without affecting alpha-T, glucose, arginine or ADMA. Baseline FMD, MDA, arginine and ADMA were unaffected by gamma-TmT (P>.05). Postprandial FMD decreased 30%-44% (P<.05) following glucose ingestion, but was maintained with gamma-TmT. Supplementation of gamma-TmT also attenuated postprandial increases in MDA that occurred following glucose ingestion. Plasma arginine decreased (P<.05) in both trials to a similar extent regardless of gamma-TmT supplementation. However, the ratio of ADMA/arginine increased time-dependently in both trials (P<.05), but to a lesser extent following gamma-TmT supplementation (P<.05). Inflammatory proteins were unaffected by glucose ingestion or gamma-TmT. Collectively, these findings support that short-term supplementation of gamma-TmT maintains VEF during postprandial hyperglycemia possibly by attenuating lipid peroxidation and disruptions in NO* homeostasis, independent of inflammation.


gamma-Tocopherol abolishes postprandial increases in plasma methylglyoxal following an oral dose of glucose in healthy, college-aged men

         (Masterjohn, Mah et al. 2012) Download

Postprandial hyperglycemia contributes to the risk of cardiovascular disease in part by increasing concentrations of the reactive dicarbonyl methylglyoxal (MGO), a byproduct of glucose metabolism. Oxidative stress increases MGO formation from glucose in vitro and decreases its glutathione-dependent detoxification to lactate. We hypothesized that the antioxidant gamma-tocopherol, a form of vitamin E, would decrease hyperglycemia-mediated postprandial increases in plasma MGO in healthy, normoglycemic, college-aged men. Participants (n=12 men; 22.3+/-1.0 years; 29.3+/-2.4 kg/m(2)) received an oral dose of glucose (75 g) in the fasted state prior to and following 5-day ingestion of a vitamin E supplement enriched in gamma-tocopherol (500 mg/day). gamma-Tocopherol supplementation increased (P<.0001) plasma gamma-tocopherol from 2.22+/-0.32 to 7.06+/-0.71 mumol/l. Baseline MGO concentrations and postprandial hyperglycemic responses were unaffected by gamma-tocopherol supplementation (P>.05). Postprandial MGO concentrations increased in the absence of supplemental gamma-tocopherol (P<.05), but not following gamma-tocopherol supplementation (P>.05). Area under the curve for plasma MGO was significantly (P<.05) smaller with the supplementation of gamma-tocopherol than without (area under the curve (0-180 min), -778+/-1010 vs. 2277+/-705). Plasma concentrations of gamma-carboxyethyl-hydroxychroman, reduced glutathione and markers of total antioxidant capacity increased after supplementation, and these markers and plasma gamma-tocopherol were inversely correlated with plasma MGO (r=-0.48 to -0.67, P<.05). These data suggest that short-term supplementation of gamma-tocopherol abolishes the oral glucose-mediated increases in postprandial MGO through its direct and indirect antioxidant properties and may reduce hyperglycemia-mediated cardiovascular disease risk.


Gamma-tocopherol may promote effective no synthase function by protecting tetrahydrobiopterin from peroxynitrite

         (McCarty 2007) Download

Oxidation of tetrahydrobiopterin by peroxynitrite in oxidant-stressed endothelium compromises nitric oxide synthase (eNOS) activity while amplifying superoxide production; this mechanism contributes prominently to the endothelial dysfunction that characterizes many common clinical disorders. As a physiological peroxynitrite scavenger, gamma-tocopherol may have the potential to protect tetrahydrobiopterin and thus preserve effective eNOS activity. Indeed, in clinical studies, supplemental gamma-tocopherol has enhanced platelet eNOS activity, and a diet high in gamma-tocopherol-rich walnuts has improved endothelium-dependent vasodilation in hypercholesterolemia. In rodents, gamma-tocopherol is reported to increase arterial expression of eNOS while up-regulating an activating phosphorylation of this enzyme. Although epidemiological efforts to link gamma-tocopherol status with coronary risk have yielded inconsistent findings, this does not rule out the possibility that high intakes of this antioxidant could provide clinical protection. The impact of supplemental gamma-tocopherol on compromised endothelium-dependent vasodilation in various disorders merits examination.

A recent brief critical review on how an increased intake of alpha-tocopherol can suppress the bioavailability of gamma-tocopher

         (Parker 2007) Download

How an increased intake of alpha-tocopherol can suppress the bioavailability of gamma-tocopherol

(Wolf 2006) Download

alpha-Tocopherol is the only form of vitamin E in vitamin supplements, whereas gamma-tocopherol is the predominant form of vitamin E in the US diet. gamma-Tocopherol has beneficial properties as an anti-inflammatory and possibly anti-atherogenic and anticancer agent. Excess a-tocopherol taken in supplements causes a reduction of gamma-tocopherol concentration in plasma. The biochemical mechanism of this effect, which is important to human nutrition, has recently been elucidated.


Cancer Prevention by Different Forms of Tocopherols

            (Yang and Suh 2012) Download

Many epidemiological studies have suggested that a low vitamin E nutritional status is associated with increased cancer risk. However, several recent large-scale human trials with high doses of alpha-tocopherol (alpha-T) have produced disappointing results. This points out the need for a better understanding of the biological activities of the different forms of tocopherols. Using a naturally occurring tocopherol mixture (gamma-TmT) that is rich in gamma-T, we demonstrated the inhibition of chemically induced lung, colon, and mammary cancer formation as well as the growth of xenograft tumors derived from human lung and prostate cancer cells. This broad anticancer activity of gamma-TmT has been attributed mainly to the trapping of reactive oxygen and nitrogen species and inhibition of arachidonic acid metabolism. Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) and the inhibition of estrogen signaling have also been observed in the inhibition of mammary cancer development. delta-T has been shown to be more active than gamma-T in inhibiting the growth of human lung cancer cells in a xenograft tumor model and the development of aberrant crypt foci in azoxymethane-treated rats, whereas alpha-T is not effective in these models. The higher inhibitory activities of delta-T and gamma-T (than alpha-T) are proposed to be due to their trapping of reactive nitrogen species and their capacity to generate side-chain degradation products, which retain the intact chromanol ring structure and could have cancer preventive activities.


The L-arginine paradox: Importance of the L-arginine/asymmetrical dimethylarginine ratio

         (Bode-Boger, Scalera et al. 2007) Download

Cardiovascular diseases (CVD) are still the most frequent cause of death in Western Europe. Pathophysiological experiments revealed in the last years that the vascular endothelium, as well as a result of the synthesis of nitric oxide (NO), is a crucial regulator of vascular function and homeostasis. The vascular endothelium plays a key role in cardiovascular physiology and pathophysiology, largely via NO-dependent processes. L-Arginine is the substrate for the endothelial NO synthase (eNOS) to generate NO. Endothelial dysfunction is caused by various cardiovascular risk factors. In most studies, acute and chronic administration of L-arginine has been shown to improve endothelial function in animal models of hypercholesterolemia and atherosclerosis. Therefore, numerous studies have been conducted to elucidate whether dietary L-arginine supplementation can augment NO production in humans and thereby improve endothelium-dependent vasodilatation. The most likely mechanism that explains the occurrence of endothelial dysfunction and the effect of L-arginine is that application of L-arginine antagonizes asymmetric dimethylarginine (ADMA), the endogenous NO synthase (NOS) inhibitor. This could solve the L-arginine paradox namely that L-arginine improves NO-mediated vascular function in vivo, although its baseline plasma concentration is about 25- to 30-fold higher than the Michaelis-Menten constant Km of the isolated, purified eNOS in vitro. Recent findings suggest that large, prospective, randomized clinical trials might be needed to identify those patients who are the most likely to benefit from L-arginine. Testing patients for ADMA and L-arginine plasma levels for calculating the L-arginine/ADMA ratio might be an adequate strategy.


References

Bode-Boger, S. M., F. Scalera, et al. (2007). "The L-arginine paradox: Importance of the L-arginine/asymmetrical dimethylarginine ratio." Pharmacol Ther 114(3): 295-306 PMID: 17482266

Dietrich, M., M. G. Traber, et al. (2006). "Does gamma-tocopherol play a role in the primary prevention of heart disease and cancer? A review." J Am Coll Nutr 25(4): 292-9 PMID: 16943450

Hensley, K., E. J. Benaksas, et al. (2004). "New perspectives on vitamin E: gamma-tocopherol and carboxyelthylhydroxychroman metabolites in biology and medicine." Free Radic Biol Med 36(1): 1-15 PMID: 14732286

Jialal, I. and S. Devaraj (2005). "High-dosage vitamin E supplementation and all-cause mortality." Ann Intern Med 143(2): 155; author reply 156-8 PMID: 16027470

Jiang, Q., I. Elson-Schwab, et al. (2000). "gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells." Proc Natl Acad Sci U S A 97(21): 11494-9 PMID: 11005841

Jiang, Q., J. Lykkesfeldt, et al. (2002). "Gamma-tocopherol supplementation inhibits protein nitration and ascorbate oxidation in rats with inflammation." Free Radic Biol Med 33(11): 1534-42 PMID: 12446211

Lee, H. J., J. Ju, et al. (2009). "Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-gamma." Clin Cancer Res 15(12): 4242-9 PMID: 19509159

Mah, E., S. K. Noh, et al. (2013). "Supplementation of a gamma-tocopherol-rich mixture of tocopherols in healthy men protects against vascular endothelial dysfunction induced by postprandial hyperglycemia." J Nutr Biochem 24(1): 196-203 PMID: 22841396

Masterjohn, C., E. Mah, et al. (2012). "gamma-Tocopherol abolishes postprandial increases in plasma methylglyoxal following an oral dose of glucose in healthy, college-aged men." J Nutr Biochem 23(3): 292-8 PMID: 21543210

McCarty, M. F. (2007). "Gamma-tocopherol may promote effective no synthase function by protecting tetrahydrobiopterin from peroxynitrite." Med Hypotheses 69(6): 1367-70 PMID: 17825498

Parker, R. S. (2007). "A recent brief critical review on how an increased intake of alpha-tocopherol can suppress the bioavailability of gamma-tocopher." Nutr Rev 65(3): 139 PMID: 17425066

Wolf, G. (2006). "How an increased intake of alpha-tocopherol can suppress the bioavailability of gamma-tocopherol." Nutr Rev 64(6): 295-9 PMID: 16808116

Yang, C. S. and N. Suh (2012). "Cancer Prevention by Different Forms of Tocopherols." Top Curr Chem PMID: 22836899