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Reply to W Cohn

Steacie Institute for Molecular Sciences National Research Council of Canada Ottawa, Ontario Canada K1A 0R6

Maret G Traber

Linus Pauling Institute Oregon State University 571 Weniger Hall Corvallis, OR 97331-6512

Herbert J Kayden

Department of Medicine New York University School of Medicine 550 First Avenue New York, NY 10016

Dear Sir:

In reference to our recent publication (1), Cohn questions the validity of our method of measuring relative bioavailability of natural (RRR) and synthetic (all-rac) -tocopherols in human tissues and whether our results are predictive of relative biopotency. In particular, Cohn states that giving both forms of vitamin E together in equal amounts, providing 75% 2R and 25% 2S forms, could overestimate the relative bioavailability of the 2R forms.

Cohn suggests that interactions between all-rac--tocopherol stereoisomers (eg, synergism) could invalidate the competitive method. However, it must be recognized that for many people supplementation with all-rac--tocopheryl acetate will itself be an uncontrolled, competitive exercise, carried out under conditions that are quite different from those used to determine animal biopotency. That is, the all-rac--tocopherol stereoisomers must compete with an unknown and variable amount of circulating, endogenous RRR--tocopherol, making it difficult to see how there could be a useful bioavailability ratio if the interactions are significant. We agree that validation of our method is important and welcome this opportunity to provide additional supporting evidence.

The official biopotency ratio for the acetate esters of natural and synthetic -tocopherol (RRR--tocopheryl acetate:all-rac--tocopheryl acetate = 1.36) is based on a small number of biological responses (primarily fetal gestation-resorption, as well as muscular dystrophy and encephalomalacia) measured in assays in a few species of vitamin E–deficient animals (rats, chicks, and rabbits). The general similarity between the different assay results, coupled with support from some high-dose, short-term bioavailability studies in humans, has been taken as evidence that a single number can adequately represent the relative biopotency of natural and synthetic vitamin E for most, if not all, animal species, including humans. Our recent study (1) provides evidence that the currently accepted biopotency value may significantly underestimate tissue bioavailability in humans, at least over the long term (ie, 1–2 y and beyond).

We applied the competitive dosing technique in a companion study of relative bioavailability in male rats (N Hidiroglou, DO Foster, GW Burton, KU Ingold, unpublished observations, 1989). Concentrations of RRR--tocopherol and all-rac--tocopherol were measured at various times in plasma and tissues of rats fed exclusively a 1:1 mixture of the acetates (at a relatively high dose of 36 mg/kg diet) over a 5-mo period. The ratio of RRR--tocopherol to all-rac--tocopherol (RRR:rac; averaged over 10 animals) varied little between tissues (except liver and plasma) and over time: 1.40 ± 0.06 in brain, 1.46 ± 0.06 in heart, 1.36 ± 0.07 in kidney, 1.47 ± 0.06 in lung, 1.46 ± 0.07 in muscle, 1.41 ± 0.07 in testis, 1.16 ± 0.06 in liver, and 1.62 ± 0.08 in plasma.

Recently, the Hoffmann–La Roche group published the results of their application of chiral chromatographic methods to determine the relative concentrations of all 8 stereoisomers of all-rac--tocopherol in plasma and several tissues of vitamin E–deficient female rats dosed only with all-rac--tocopheryl acetate daily for 3 mo (2). Averaging their calculated RRR:rac over time gives 1.38 for brain, 1.41 for adipose tissue, 1.18 for liver, and 1.61 for plasma. Clearly, there is good agreement between the 2 methods when comparisons are possible, despite the fact that, as Cohn remarked (1), the 2R-2S dose ratio is 3:1 in our competitive method and 1:1 in the traditional method. Thus, the suggestion that the competitive method overestimates the relative RRR:rac bioavailability is not supported by these experimental findings.

Furthermore, it is apparent that the relative bioavailability values in nonhepatic rat tissues are all close to rat biopotency values [eg, 1.26–1.41 for fetal resorption and 1.43–1.52 for myopathy (3)]. The closeness of these tissue bioavailability ratios to the biopotency ratios is consistent with bioavailability being the dominant cause of the difference in biopotency in rats. This strengthens the observation of Weiser et al (2), with respect to their own findings, that "the results are in agreement with the hypothesis that for -tocopherol stereoisomers, biopotency differences are related to corresponding differences of -tocopherol concentrations."

In rats the maximum RRR:rac is observed in plasma (1.5–1.7), in both continuous feeding and single-dose, competitive studies, and tissue values do not exceed 1.5 over a period of 5 mo of continuous dosing. In humans, the ratio in plasma starts at <1.5 during dosing and rises to a limiting value of 2 several days after dosing, regardless of the total dose (30, 150, or 300 mg/d) and dosing period, and is maintained over a wide range of plasma concentrations (up to the analytic sensitivity of the method, 3 mo after 8 continuous days of dosing at 300 mg/d) (1). Nonhepatic tissue RRR:rac values (1.4–1.6) after short-term dosing (<5 wk) generally reflect the lower plasma values observed during dosing and the proportion of labeled -tocopherol greatly lags behind the corresponding proportion in plasma. In contrast, the results obtained from 2 terminally ill patients indicate, especially for the patient receiving 300 mg/d for almost 2 y, a long-term trend toward equilibration of the labeled -tocopherol between plasma and tissues, with regard both to the RRR:rac, which tends to a maximum value of 2, and to the fraction of labeled -tocopherol. Also noteworthy is an even higher ratio (3.4) observed in fetal cord blood obtained from women fed a 1:1 mixture of RRR- and all-rac--tocopheryl acetate just before giving birth (4).

The higher RRR:rac observed in human plasma, and eventually in tissues, implies that a greater degree of discrimination occurs in humans than in rats. The rapid disappearance of SRR--tocopherol from human plasma after a single 1:1 dose of RRR- and SRR--tocopheryl acetate (ie, ambo--tocopherol) (5, 6) suggests that most, if not all, of the 2S forms are eventually eliminated because the behavior of SRR--tocopherol more or less approximates that of the four 2S stereoisomers (2). If the four 2R forms behave like RRR--tocopherol (2), a limiting RRR:rac value of 2 will result.

The main source of discrimination is likely the liver tocopherol transfer protein (TTP), which is of major importance for vitamin E homeostasis in humans (7). Indeed, rat TTP shows an 2-fold greater affinity for RRR- than for all-rac--tocopherol (8). Determination of the extent to which TTP controls recycling and redistribution, as well as uptake, of vitamin E would reveal its importance in controlling tissue bioavailability. We suggest that reassessment of relative bioavailability for human nutritional and health needs is appropriate, bearing in mind that most benefits of the vitamin are of a long-term nature.

REFERENCES

1. Burton GW, Traber MG, Acuff RV, et al. Human plasma and tissue -tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E. Am J Clin Nutr 1998;67:669–84.[Abstract]
2. Weiser H, Riss G, Kormann AW. Biodiscrimination of the eight -tocopherol stereoisomers results in preferential accumulation of the four 2R forms in tissues and plasma of rats. J Nutr 1996;126:2539–49.
3. Weiser H, Vecchi M, Schlachter M. Stereoisomers of -tocopheryl acetate. III. Simultaneous determination of resorption-gestation and myopathy in rats as a means of evaluating biopotency ratios of all-rac- and RRR--tocopheryl acetate. Int J Vitam Nutr Res 1985;55:149–58.[Medline]
4. Acuff RV, Dunworth RG, Webb LW, Lane JR. Transport of deuterium-labeled tocopherols during pregnancy. Am J Clin Nutr 1998;67:459–64.[Abstract]
5. Traber MG, Burton GW, Ingold KU, Kayden HJ. RRR- and SRR--tocopherols are secreted without discrimination in human chylomicrons, but RRR--tocopherol is preferentially secreted in very low density lipoproteins. J Lipid Res 1990;31:675–85.[Abstract]
6. Traber MG, Burton GW, Hughes L, et al. Discrimination between forms of vitamin E by humans with and without genetic abnormalities of lipoprotein metabolism. J Lipid Res 1992;33:1171–82.[Abstract]
7. Ouahchi K, Arita M, Kayden H, et al. Ataxia with isolated vitamin E deficiency is caused by mutations in the -tocopherol transfer protein. Nat Genet 1995;9:141–5.[Medline]
8. Catignani GL. Hepatic -tocopherol-binding protein. Methods Enzymol 1980;67:117–22.[Medline]

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