Journal of the American College of Nutrition, Vol. 23, No. 3, 233-238 (2004)
Published by the American College of Nutrition
Alpha and Gamma Tocopherols in Cerebrospinal Fluid and Serum from Older, Male, Human Subjects
Govind T. Vatassery, PhD,
Adityanjee, MD,
Hung T. Quach, BS,
W. Ed Smith, BS,
Michael A. Kuskowski, PhD and
Dean Melnyk, MD, PhD
Research Service (G.T.V., H.T.Q., W.E.S.), University of Minnesota, Minneapolis, Minnesota
GRECC (G.T.V., M.A.K.), University of Minnesota, Minneapolis, Minnesota
Anesthesiology Section, Surgery Service (D.M.), University of Minnesota, Minneapolis, Minnesota
Veterans Administration Medical Center, Department of Psychiatry (G.T.V., A.), University of Minnesota, Minneapolis, Minnesota
Graduate Program in Neuroscience (G.T.V.), University of Minnesota, Minneapolis, Minnesota
Department of Anesthesiology (D.M.), University of Minnesota, Minneapolis, Minnesota
Address correspondence to: G. T. Vatassery, PhD, Research Service, 151, V. A. Medical Center, Minneapolis Minnesota 55417. E-mail: vatas001{at}tc.umn.edu
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ABSTRACT
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Objective: The major forms of vitamin E in human physiological fluids are alpha and gamma tocopherols which exhibit different biological activities under a variety of assay conditions. The goal of this study was to obtain indirect information about the transport of tocopherols across the blood/spinal fluid barrier by comparing the concentrations of alpha and gamma tocopherols in serum and cerebrospinal fluid (CSF).
Methods: CSF and serum samples were obtained simultaneously from 28 human, male subjects excluding those with known pathology during the performance of spinal anesthesia procedures. The samples were centrifuged and frozen, and analyzed for tocopherols by HPLC with electrochemical detection.
Results: The concentrations of alpha and gamma tocopherols in CSF correlated significantly with their respective concentrations in serum. This would be expected since these nutrients have to be supplied by diet to serum followed by transport to the brain. The ratios of alpha to gamma tocopherols in the CSF and serum were highly correlated. High concentrations of alpha in serum tended to suppress gamma in both serum and CSF.
Conclusions: These data suggest that the processes involved in the entry of tocopherol from blood to the CSF do not discriminate between the alpha and gamma tocopherols. In contrast, alpha tocopherol is highly preferred during the packaging of plasma lipoproteins by the liver. Our data also suggest that alpha and gamma tocopherols will be available to the human brain via transport from blood.
Key words: alpha tocopherol, gamma tocopherol, vitamin E, cerebrospinal fluid, blood brain barrier, antioxidants, elderly male humans
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INTRODUCTION
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The transport of trace nutrients across the blood brain barrier has been examined by numerous investigators. Blood/brain and blood/cerebrospinal fluid (CSF) barriers are known to have distinct transport systems for water-soluble nutrients such as ascorbate and thiamine [1]. The transport of fat-soluble vitamins would be more complex since lipoproteins as well as specific carrier proteins could be involved in the process. Lipoproteins have different distributions in human CSF and serum. For example, it has been reported that apolipoproteins AI and E are present in CSF whereas apolipoprotein B is absent [2,3]. More recently, Koch et al. [4] confirmed that apoE and apoAI are the major lipoproteins in CSF with AII, D, H and J also being present. The transport of lipid-soluble nutrients carried by the different lipoproteins will be influenced by the availability and concentrations of lipoproteins in the CSF compartment.
Vitamin E is the generic name for a group of compounds that include four tocopherols and four tocotrienols. However, human plasma contains primarily alpha and gamma tocopherols. Hence it would be of interest to study whether there is any discrimination between these molecular forms of vitamin E at the blood/brain/CSF barriers. Even though the majority of investigations on vitamin E has focused on alpha tocopherol, the biological effects of gamma tocopherol have been studied over many decades. Bieri and Poukka Evarts [5] noted that gamma tocopherol is the main component of US diets and observed that gamma tocopherol was eliminated from tissues much faster than alpha tocopherol. In a review, Jiang et al. [6] concluded that gamma tocopherol may have a special role in detoxifying reactive nitrogen species, as an anti-inflammatory agent and in protecting against cardiovascular disease and prostate cancer. Saldeen et al. [7] have shown that gamma tocopherol is more effective than alpha in decreasing platelet aggregation and delaying intra-arterial thrombus formation in humans. Thus additional information on the distribution and biological activities of these two major tocopherols in humans is needed.
Data on the transport and uptake of substances by human brain can only be obtained indirectly. Many investigators have used CSF as an accessible fluid which reflects the composition of brain extracellular fluid. The goal of this study is to examine the relationships between alpha and gamma tocopherols in human cerebrospinal fluid and serum in order to learn more about the transport of these specific forms of vitamin E from blood into brain in humans.
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MATERIALS AND METHODS
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Chemicals
The chemicals used were of reagent grade purity from standard sources. Solvents for chromatography were HPLC grade from Burdick and Jackson Laboratories, Inc., Muskegon, MI. Alpha and gamma tocopherols were obtained from Kodak Laboratory Chemicals, Rochester, NY. Absolute ethanol was obtained from Midwest Solvents Company, Pekin, IL, and was redistilled prior to use. Most of the other reagent grade chemicals were from Sigma Chemicals, St. Louis, MO.
Human Subjects
This study was approved by the Institutional Review Board of the Minneapolis Veterans Administration Medical Center. The subjects signed standard informed consent forms approved by the committee. Spinal fluid and blood samples were collected from over 28 human male subjects (mean age of 70.5 years (S.D. 8.7); range 49 to 87 years) when they underwent spinal anesthesia procedures as part of their clinical care. They did not have any known metabolic or lipid abnormalities, psychiatric or neurologic symptoms, denied any history of smoking and were not taking any vitamin supplements in high doses. The demographics of the VA patient population resulted in the subjects being all males in this older age group.
Determination of Tocopherols and Cholesterol
The methods for determination of tocopherols by liquid chromatography [8] and for cholesterol by gas chromatography [9] have been published. The total tocopherols and cholesterol were determined after saponification of the fluid samples. In order to determine the unesterified portions of the compounds we used an extract made in the presence of sodium dodecyl sulfate as described by Burton et al. [10].
Briefly, 2 mL ethanol containing 0.025% (w/v) butylated hydroxytoluene(BHT) and 0.1 mL of 30% (w/v) ascorbic acid were pipetted into tubes containing the serum and CSF samples. The mixture was saponified at 60°C for 30 minutes after the addition of 1 mL of 10% potassium hydroxide solution. Tubes were cooled and 2 mL of water was added followed by 2 mL of hexane containing 0.025% (w/v) BHT. Tocopherols and the cholesterol compounds were extracted into the hexane phase by vortexing the samples for one minute. One portion of the hexane phase was separated out and evaporated down under a stream of nitrogen. The residue was redissolved in mobile phase and analyzed by reverse phase liquid chromatography using the following conditions: column = ultrasphere ODS, 5 microns, 4.6 x 150 mm (Beckman Instruments, Fullerton, CA, USA); mobile phase = methanol: water, (94.5 : 5.5) with 7.5 mM sodium dihydrogen phosphate (final concentration); flow rate = 2.7 mL/minute. The tocopherols and tocopherolquinone were detected electrochemically: Coulochem 5100 A detector, 5011 analytical cell with detector 1 at –0.25 V and detector 2 at +0.55 V and 5021 conditioning cell at –0.75V.
Another portion of the hexane extract was used for determination of cholesterol and cholesterol esters. After evaporation of the solvent, trimethylsilyl-ether derivative of cholesterol was prepared and analyzed by gas liquid chromatography with flame ionization detection using a capillary column under the following conditions: DB1 column, 30 m x 0.32 mm, film thickness 0.25 µm; temperature programming — oven temperature, initial 50C, initial time 3 minutes, program rate 30 C per minute, final value 290 C, second program rate 1 C per minute, final temperature 300 C, and keep at 300 C for 5 minutes. Under these conditions the observed retention times for cholesterol and cholestane (internal standard) were 17.33 and 14.83 minutes, respectively.
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RESULTS
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As we have found in our previous study, there was little, if any, tocopherol esters in either the serum or spinal fluid samples [11]. Therefore, unlike cholesterol, alpha tocopherol is transported exclusively as the free molecule in both serum and cerebrospinal fluid.
The mean levels of alpha and gamma tocopherols and total cholesterol in the CSF and sera samples are given in Table 1.
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Table 1. Concentrations of Alpha and Gamma Tocopherols and Total Cholesterol in Sera and CSF of Adult, Male, Human Volunteers
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Many investigators have studied changes in CSF vitamin E concentrations in different disease states. However, most of these reports including our own earlier publication [11] involve determination of alpha tocopherol only. Therefore, one can only compare the reported values for CSF alpha tocopherol concentrations among the different studies. DeBustos et al. [12] found the CSF alpha tocopherol to be 30.1 ± 11.6 nM (n = 78), while Schippling et al. [13] found the concentration to be 56.7 ± 28.4 nM (n = 29). These levels are quite comparable with the mean value of 42.1 ± 17 nM observed in the current study. Furthermore, total cholesterol concentrations in plasma and CSF in our study were comparable to those obtained by Koch et al. [4], who reported mean concentrations of 5700 and 15.5 µM in plasma and CSF, respectively.
The relationship between the concentrations of alpha tocopherol in the serum and CSF is shown in Fig. 1. There was a statistically significant correlation between the two variables (r = 0.56, n = 28, p = 0.002). (After statistical analysis, since the line should go through the origin for theoretical reasons, a linear regression line through the origin has been drawn in Figs. 1 to 4.) The influence of age and total cholesterol on this correlation was also examined. The partial correlation coefficients controlling for age and total cholesterol were 0.57 and 0.61, respectively. Thus this relationship is not altered by either age or total cholesterol in serum.
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Fig. 1. Alpha tocopherol concentrations in serum and cerebrospinal fluid from human subjects (n = 28). Samples of blood and CSF were obtained from human, male subjects, and the tocopherol concentrations were determined by HPLC with electrochemical detection.
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Fig. 4. The relationship between the ratio of alpha to gamma tocopherols in serum and alpha tocopherol concentrations in CSF (n = 28). Samples of blood and CSF were obtained from human, male subjects, and the tocopherol concentrations were determined by HPLC with electrochemical detection. The ratios between the alpha and gamma tocopherol concentrations were then calculated and graphed.
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Fig. 2 illustrates the relationship between gamma tocopherol in serum and CSF. In this case also, the correlation is highly significant (r = 0.68, p = <0.001). As in the previous case, we calculated partial correlation coefficients. Controlling for age the correlation coefficient was 0.68, whereas controlling for total cholesterol the correlation coefficient was 0.69. Therefore, the relationship between serum and CSF gamma tocopherols also is not affected by either age or serum total cholesterol.
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Fig. 2. Gamma tocopherol concentrations in serum and cerebrospinal fluid from human subjects (n = 28). Samples of blood and CSF were obtained from human, male subjects, and the tocopherol concentrations were determined by HPLC with electrochemical detection.
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Next, the ratios of alpha and gamma tocopherol concentrations in both serum and CSF were calculated. These derived parameters were then plotted in Fig. 3. There was a highly significant positive correlation between the two ratios (r = 0.85, p = <0.001). This suggests that both alpha and gamma tocopherols are being transported from serum to the cerebrospinal fluid compartment by closely similar mechanisms. In other words, it is quite likely that the processes involved do not discriminate between alpha and gamma at the blood brain barrier.
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Fig. 3. The correlation between the ratios of alpha to gamma tocopherol concentrations in human serum and cerebrospinal fluid samples (n = 28). Samples of blood and CSF were obtained from human, male subjects, and the tocopherol concentrations were determined by HPLC with electrochemical detection. The ratios between the alpha and gamma tocopherol concentrations were then calculated and used in the figure.
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We examined how the ratio of alpha to gamma tocopherols in serum influenced the concentrations of alpha or gamma tocopherol in CSF. There was a significant positive correlation (r = 0.75, p 
0.001) between serum alpha to gamma tocopherol ratios versus CSF alpha tocopherol (Fig. 4). This would be expected because a) alpha tocopherol is the major component of both fluids and b) there is a positive correlation between alpha tocopherol concentrations in serum and CSF.
An examination of the relationship between CSF gamma tocopherol concentrations and the serum alpha to gamma tocopherol ratios shows a more complex relationship (see Fig. 5). One can explain this only after considering the effect of alpha tocopherol administration upon gamma tocopherol concentrations in serum. It has been well-established that the dietary intake of high concentrations of alpha tocopherol is associated with sharp declines in gamma tocopherol in serum [14]. This observation leads to two possibilities: a) when the alpha to gamma ratio is high, the gamma concentrations will tend to go down substantially in the CSF, and b) at the lowest levels of alpha to gamma tocopherol ratios, one would expect that the concentrations of gamma tocopherol in CSF would be almost independent of the ratio. This is the type of relationship that one observes in Fig. 5.
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Fig. 5. The relationship between the ratio of alpha to gamma tocopherols in serum and gamma tocopherol concentrations in CSF (n = 28). Samples of blood and CSF were obtained from human, male subjects, and the tocopherol concentrations were determined by HPLC with electrochemical detection. The ratios between the alpha and gamma tocopherol concentrations were then calculated and plotted. The data were fitted to a polynomial regression line.
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The above analysis based on data from literature is confirmed by an examination of our own data on the relationship between serum alpha tocopherol and CSF gamma concentrations (Fig. 6). At low concentrations of alpha tocopherol, the gamma tocopherol concentrations are almost independent of serum alpha tocopherol. However, at higher concentrations of serum alpha tocopherol, CSF gamma tocopherol concentrations are extremely low. If the data are subjected to a linear regression there is significant decline in CSF gamma tocopherol as the serum alpha tocopherol concentrations go up (r = –0.43, p = 0.02).
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Fig. 6. Concentrations of alpha tocopherol in serum and gamma tocopherol in CSF of human subjects (n = 28). Samples of blood and CSF were obtained from human, male subjects, and the tocopherol concentrations were determined by HPLC with electrochemical detection.
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DISCUSSION
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Cerebrospinal fluid is a supplier of essential nutrients to the brain [15]. The final concentrations of nutrients in CSF results from the establishment of complex equilibria at the blood-brain and blood-CSF barriers. Hence any changes in the concentrations of either alpha or gamma tocopherol in CSF would reflect altered nutritional status of the brain with respect to vitamin E, which has to be transported from blood. The delivery of micronutrients across the blood brain barrier is controlled by several types of processes. Spector and collaborators [1] concluded that carrier-mediated mechanisms for entry of several nutrients are much more important than simple diffusion processes. Pardridge and coworkers [16] proposed that protein-bound ligands may be stripped off plasma proteins by brain because of the rapid nature of ligand dissociation, the diffusion of ligand into brain as well as the rapid transit of blood through capillaries. These kinetic considerations will make the relationships between plasma and spinal fluid (representing the brain extracellular fluid) concentrations of lipid-soluble substances such as tocopherols fairly complex. Nonetheless, the concentrations of substances in CSF will be controlled in large part by the respective concentrations in serum. This is in agreement with our data in Figs. 1 and 2 that show that CSF concentrations of the two tocopherols are significantly correlated with the respective serum concentrations.
Even though our data will not allow the deciphering of a specific mechanism of transport of tocopherols between plasma and CSF in humans, the results of a few studies on tocopherol transport are of interest. Kostner et al. [17] observed that human plasma phospholipid transport protein can accelerate the exchange/transfer of alpha tocopherol between lipoproteins and cells. Reports from the laboratory of Lagrost have shown that phospholipid transport protein can facilitate transfer of vitamin E from VLDL to HDL in plasma even though the data suggested that other proteins may also be participating in the process [18]. A few experimental animal studies have examined the mechanisms of transport of vitamin E across the blood brain barrier. The cerebrovascular endothelial cells are known to be the major sites of the blood brain barrier, and some investigators have used these cells as an in vitro model for the barrier. Using this system Goti et al. [19] found that high density lipoprotein may have an important role in supplying vitamin E to the brain. The same group also reported that the uptake of alpha tocopherol across the blood brain barrier was modulated by lipoprotein lipase since alpha tocopherol uptake into brain was significantly lower in lipoprotein lipase-deficient mice compared with contols [20]. These investigations and our data will support the hypothesis that tocopherols are transported from blood to CSF as a component of a lipoprotein complex such as HDL. Whether any of the processes involved discriminate between alpha and gamma tocopherols is not completely understood. It is interesting to note that Tran and Chan [21] found that human endothelial cells from umbilical veins do discriminate between these compounds. Similar data using human cerebrovascular endothelial cells have not been obtained. Also, cerebrovascular endothelial cells are only a model system for the blood brain barrier; the final equilibrium concentrations of substances such as alpha and gamma tocopherols in CSF will be dependent on several factors including turnover rates within the brain and the permeability of the blood-brain-CSF barriers.
Our observations show that there is an important difference between the establishment of tocopherol concentrations in plasma and CSF. It is known that the liver preferentially incorporates alpha rather than gamma tocopherol during the packaging of lipoproteins and this effect is mediated by the alpha tocopherol transfer protein [22,23]. However, once the tocopherols are present in serum our data suggest that there is little differentiation between alpha and gamma tocopherol molecules at the site of the blood brain barrier in humans. Obviously, this conclusion is derived indirectly from studies of concentrations of tocopherols in serum and CSF. Much more work needs to be done to establish the generality of this phenomenon.
The deposition of alpha or gamma tocopherols in brain after dietary treatment has been the subject of some investigations. Clement et al. [24] fed either alpha or gamma tocopherol to vitamin E deficient rats. They found that significant concentrations of gamma tocopherol accumulated in tissues including brain upon feeding of gamma tocopherol; but the extent of accumulation was much less than that with alpha tocopherol feeding. The same investigators also observed that when both alpha and gamma tocopherols were fed together to the rats the increase in alpha tocopherol in tissues was much higher than after feeding of alpha tocopherol alone [25]. Thus gamma tocopherol has a synergistic effect on enhancing tissue alpha tocopherol concentrations. These reports suggest the complexity of the processes involved in the deposition of tocopherols into the brain. The extent of applicability of these observations in experimental animals to humans is unknown at this time.
It should be noted that our patient population consisted of elderly subjects who were undergoing spinal anesthesia as part of their routine care. We have eliminated numerous individuals who had disorders that were well documented. Thus these subjects could be considered "normal". However, the subjects tended to be in the older age group. Hence the general applicability of these findings to humans of all ages need to be established by additional investigations.
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CONCLUSIONS
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Our data support the hypothesis that there is no discrimination between alpha and gamma tocopherols at the blood-brain-CSF barrier sites. Goti et al. [19] have also observed that the eight stereoisomers of alpha tocopherol were transported at similar rates across porcine brain capillary endothelial cells. Thus our observations are in agreement with those of Goti et al. [19] who used experimental animal cells. If both alpha and gamma tocopherols are important for brain function, our data suggest that blood plasma could provide both tocopherols to the brain. Hence future clinical trials involving the use of tocopherols in the treatment of brain disorders could be designed using dietary administration of the necessary concentrations of alpha or gamma tocopherol. However, one should also consider the potential differences in turnover of the two tocopherols in tissues [5]. The use of gamma tocopherol with or without alpha tocopherol could become more important with reports in the literature suggesting that gamma tocopherol as well as mixed tocopherols may have unique properties. For example, Liu et al. [26] reported recently that mixed tocopherols are more potent in preventing platelet aggregation than alpha tocopherol alone. These and other studies discussed earlier would lead to an enhanced interest in the use of both alpha and gamma tocopherol in human clinical trials. Our current observations suggest that both alpha and gamma tocopherol would reach the human brain from the serum compartment without either compound being preferred during the uptake process.
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ACKNOWLEDGMENTS
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These investigations were supported by research funds from the Department of Veterans Affairs, the Natural Source Vitamin E Foundation and the Henkel Corporation.
Received June 19, 2003.
Accepted September 10, 2003.
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ABSTRACT
INTRODUCTION
