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Gamma-tocopherol garners speculation

The spate of recent studies impugning the safety and efficacy of alpha-tocopherol1 have illuminated the promise of its sibling, gamma-tocopherol. In discussing the findings of increased risk of heart failure among persons asked to supplement with alpha-tocopherol over an average period of seven-plus years, the HOPE-TOO study authors suggested it could be due to alpha?s ability to ?displace? gamma, ?disrupting the natural balance of antioxidant systems.?2

The predominant tocopherol vitamer present in European diets is alpha while in American diets it is gamma,3,4,5 yet alpha is invariably used as a fortificant and in dietary supplements. Although observational studies have linked higher alpha/vitamin E intakes and blood concentrations with decreased risk of cardiovascular disease, most intervention trials with pure alpha have yielded modest to disappointing results.6 The retrospectively myopic focus on alpha as the agent in these studies is offset by a compelling suite of preclinical studies and pilot clinicals that compel a look at gamma.

Animals receiving a gamma-enriched diet for 10 days showed significantly greater antioxidant and cardioprotective effects than animals receiving alpha.7 Four weeks of feeding a gamma-supplemented diet (adult human intake equivalent of 544mg [82IU] of gamma) had a pronounced anti-inflammatory effect in animals without altering tissue alpha content, although it was not compared to an equal alpha-supplemented diet.8

Because gamma is available in only ?research? quantities, chronic supplementation studies with humans are lacking. Single-dose studies have shown that (pure) gamma is more rapidly metabolised into a water-soluble derivative called gamma-CEHC (alpha is metabolized into alpha-CEHC) and excreted in the urine, with alpha being preferentially retained in the plasma.9,10 Gamma-CEHC has been shown to have sodium excretion-promoting action.11

Chronic supplementation studies attempting to discern the bioactivity of gamma have been limited to the use of mixed tocopherol (MT) compositions, highest in gamma.

In one study, healthy subjects were supplemented with Cardi-E (100mg gamma, 40mg delta-tocopherol and 10mg alpha), or 100mg all-rac alpha-tocopherol acetate for eight weeks.12 Platelet aggregation and an indirect measure of nitric oxide production was improved to a significantly greater extent in the MT group over the alpha group, although the alpha dose was low relative to previous studies.

Another study supplemented with either 300mg of RRR-alpha-tocopherol or MT (60 per cent gamma, 28 per cent delta and 10 per cent alpha; natural isomers) to both chronic haemodialysis patients and healthy subjects for two weeks.13 In the healthy subjects, blood gamma and gamma-CEHC concentrations increased modestly, with alpha-CEHC displaying only a transient elevation. Among the haemodialysis patients, blood gamma did not increase while both alpha- and gamma-CEHC concentrations increased.

Whether gamma-tocopherol emerges as the next generation of vitamin E depends on both scaleable production of gamma-rich and gamma-pure compositions and a series of systematic head-to-head comparison clinical trials in a variety of health and disease states. Innovative compositions with sesame lignans,14 and perhaps an avoidance of flax lignans like SDG may favourably alter gamma?s pharmacology.

Anthony Almada, MSc, is president and chief scientific officer of IMAGINutrition Inc. Respond:

1. Miller ER, III, et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005; 142:37-46.
2. The HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005; 293:1338-47.
3. Jiang Q, et al. Gamma-tocopherol, the major form of vitamin E in the U.S. diet, deserves more attention. Am J Clin Nutr 2001; 74:714-22.
4. White E, et al. Correlates of serum alpha- and gamma-tocopherol in the Women's Health Initiative. Ann Epidemiol 2001; 11:136-44.
5. Wagner KH, et al. Gamma-tocopherol ? an underestimated vitamin? Ann Nutr Metab 2004; 48:169-88.
6. Gaziano JM. Vitamin E and cardiovascular disease: observational studies. Ann NY Acad Sci 2004;1031: 280-91.
7. Saldeen T, et al. Differential effects of alpha- and gamma-tocopherol on low-density lipoprotein oxidation, superoxide activity, platelet aggregation and arterial thrombogenesis. J Am Coll Cardiol 1999; 34:1208-15.
8. Jiang Q, et al. Gamma-tocopherol supplementation inhibits protein nitration and ascorbate oxidation in rats with inflammation. Free Rad Biol Med 2002; 33:1534-42.
9. Galli F, et al. Gamma-tocopherol metabolism and its relationship with alpha-tocopherol in humans: A stable isotope supplementation study. BioFactors 2001; 15:65?9.
10. Leonard SW, et al. Studies in humans using deuterium-labeled alpha- and gamma-tocopherols demonstrate faster plasma gamma-tocopherol disappearance and greater gamma-metabolite production. Free Rad Biol Med 2005; 38:857-66.
11. Wechter WJ, et al. A new endogenous natriuretic factor: LLU-alpha. Proc Natl Acad Sci USA 1996; 93:6002-7.
12. Liu M, et al. Mixed tocopherols inhibit platelet aggregation in humans: potential mechanisms. Am J Clin Nutr 2003; 77:700-6.
13. Frank J, et al. Dietary secoisolariciresinol diglucoside and its oligomers with 3-hydroxy-3-methyl glutaric acid decrease vitamin E levels in rats. Br J Nutr 2004; 92:169-76.
14. Frank J, et al. Consumption of sesame oil muffins decreases the urinary excretion of tocopherol metabolites in humans. Ann NY Acad Sci 2004; 1031:365-7.

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