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-Tocopherol Decreases -Tocotrienol but Not 
-Tocotrienol Concentration in Rats
Department of Food and Nutrition, Sugiyama Jogakuen University, Chikusa-ku, Nagoya, Japan and * Eisai Co. Ltd., Bunkyo-ku, Tokyo, Japan
3To whom correspondence should be addressed. E-mail: kanaey{at}food.sugiyama-u.ac.jp
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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- and 
-tocotrienols accumulate in adipose tissue and skin but not in plasma or other tissues of rats fed a tocotrienol-rich fraction extracted from palm oil containing -tocopherol and - and -tocotrienols. To clarify the nature of tocotrienol metabolism, we studied the distribution of - or -tocotrienol in rats fed - or -tocotrienol without -tocopherol, and the effect of -tocopherol on their distribution. Wistar rats (4-wk-old) were fed a diet with 50 mg -tocotrienol/kg alone or with 50 mg -tocopherol/kg in expt. 1, and a diet with 50 mg -tocotrienol/kg alone or with 50 mg -tocopherol/kg in expt. 2, for 8 wk. -Tocotrienol was detected in various tissues and plasma of the rats fed -tocotrienol alone, and the -tocotrienol concentrations in those tissues and plasma decreased (P < 0.05) by the dietary -tocopherol in the rats fed -tocotrienol with -tocopherol. However, -tocotrienol preferentially accumulated in the adipose tissue and skin of the rats fed -tocotrienol alone, and the dietary -tocopherol failed either to decrease (P 
0.05) -tocotrienol concentrations in the adipose tissue and skin or to increase (P 0.05) in the urinary excretion of 2,7,8-trimethyl-2(2'-carboxymethyl)-6-hydroxycroman, a metabolite of -tocotrienol, in the rats fed -tocotrienol with -tocopherol. These data suggest that -tocopherol enhances the -tocotrienol metabolism but not the -tocotrienol metabolism in rats.
KEY WORDS: • adipose tissue • rats • skin • tocopherol • tocotrienol • vitamin E
Vitamin E is a potent fat-soluble antioxidant that inhibits lipid peroxidation in biological membranes. In nature, compounds with vitamin E activity are -, ß-, - or 
-tocopherols and -, ß-, - or -tocotrienols. The chemical properties of these vitamin E isoforms include antioxidative activities. The antioxidative activities of -tocotrienol, which inhibit lipid peroxidation in rat microsomes and mitochondria, and the oxidation of dioleoylphosphatidylcholine liposomes, are higher than those of -tocopherol (1
–4
). Tocotrienol has been suggested to exert a hypocholesterolemic or antiatherosclerotic effect in humans, rats and mice (5
–10
), and a proliferation-suppressive effect in human breast cancer cells (11
–13
), mouse mammary epithelial cells (14
,15
) and murine melanoma cells (16
). Newaz and Nawal (17
) have reported that -tocotrienol prevents an increase in the blood pressure of spontaneously hypertensive rats. Although the various biological and physiological importance of tocotrienol has been suggested, the nature of tocotrienol metabolism remains unclear.
Dietary vitamin E isoforms are absorbed in the intestine and carried to the liver as a result of the uptake of chylomicron remnants (18
). There is no discrimination between -tocopherol and other isoforms during the absorption and chylomicron secretion by the intestine (19
,20
). -Tocopherol transfer protein (-TTP)4, tocopherol-associated protein and tocopherol-binding protein are the tocopherol-regulatory proteins that determine the tissue tocopherol levels (21
). It is thought that -TTP plays an important role in the discrimination of vitamin E isoforms. -TTP catalyzes -tocopherol secretion by a novel non-Golgi–mediated pathway in liver cells, and -tocopherol is incorporated into VLDL and subsequently transported to the various tissues by lipoproteins (22
). The other isoforms of vitamin E such as tocotrienol and -tocopherol are excreted because their affinity for -TTP is low. The excess amounts of -tocopherol and -tocotrienol are metabolized to 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxycroman (-CEHC), and -tocopherol, and -tocotrienol are metabolized to 2,7,8-trimethyl-2(2'-carboxyethyl)-6-hydroxycroman (-CEHC) (23
–25
). Both - and -CEHC are excreted into urine in humans and rats. Recently, it has been suggested that the 
-oxidation of tocopherol, the initiating and rate-limiting step of the tocopherol metabolism to - and -CEHC, is catalyzed by some cytochrome P450 (CYP) isoforms (26
–29
).
The discrimination of vitamin E isoforms by -TTP, however, does not completely explain the tocotrienol distribution. Tocotrienol shows a tissue-specific accumulation in rats, mice and hamsters, although -tocopherol accumulates in the various tissues and plasma. Hayes et al. (30
) have shown that - and -tocotrienols are present in the adipose tissue of hamsters fed a diet containing - and -tocotrienols. Podda et al. (31
) have shown that high levels of - and -tocotrienols accumulated in the skin of hairless mice fed a commercial diet containing a small amount of tocotrienols. We also have shown that - and -tocotrienols are present in the adipose tissue and skin of rats, nude mice and hairless mice fed a diet containing the tocotrienol-rich fraction (TRF) extracted from palm oil containing -tocopherol and - and -tocotrienols (32
,33
). However, little is known about the precise mechanism of tocotrienol metabolism. In this study, we examined the distribution of - or -tocotrienol without -tocopherol in rats fed a diet containing - or -tocotrienol. A diet of -tocopherol lowers the -tocopherol concentration in rats (34
). We also examined the effect of dietary -tocopherol on - or -tocotrienol concentration.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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- and -Tocotrienols used as standards were purchased from Merck (Tokyo, Japan). - and -Tocotrienols added to the diet, - and -tocopherols, and - and -CEHC used as standards were generously donated by Eisai (Tokyo, Japan).
Animals and diets.
Male Wistar rats (3-wk-old) were purchased from Japan SLC (Shizuoka, Japan). They were maintained at 24.5°C with a 12-h light cycle (lights on from 0800 to 2000h), and allowed free access to water and food. The rats were fed a commercial diet (CE-2; Japan Clea, Tokyo, Japan) for 7 d before the start of each experiment and then fed the experimental diet for 8 wk. The composition of the experimental diet is shown in Table 1
. The rats were killed between 1000 and 1200 h, and all procedures were performed in accordance with the Animal Experimentation Guidelines of Nagoya University.
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The rats were fed a diet without vitamin E (the deficient group, n = 6), a diet containing 50 mg -tocopherol/kg (the -Toc group, n = 6), a diet containing 50 mg -tocotrienol/kg (the -Toc3 group, n = 6) or a diet containing 50 mg -tocotrienol/kg and 50 mg -tocopherol/kg diet (the -Toc3 + -Toc group, n = 6) for 8 wk. For the last 24 h, the rats were deprived of food and urine samples were collected in a test tube kept cool with dry ice as soon as the rats urinated on a plastic tray under each cage. Thereafter, the rats were anesthetized with sodium pentobarbital, and the blood was drawn from the heart using a heparinized needle and syringe. The urine was lyophilized and stored at -80°C under nitrogen until determination of the - and -CEHC concentrations. The liver, kidney, heart, lung, brain, muscle, perirenal adipose tissue, epididymal fat and dorsal skin were taken and stored at -80°C until the vitamin E and thiobarbituric acid-reactive substance (TBARS) levels were determined.
Experiment 2.
The rats were fed a diet containing 50 mg -tocopherol/kg (the -Toc group, n = 6), a diet containing 50 mg -tocotrienol/kg (the -Toc3 group, n = 6) or a diet containing 50 mg -tocotrienol/kg and 50 mg -tocopherol/kg (the -Toc3 + -Toc group, n = 6) for 8 wk. After 24 h of food deprivation, the rats were anesthetized with sodium pentobarbital, and the blood was drawn from the heart using a heparinized needle and syringe. The tissues, plasma and urine were sampled and handled as described for expt. 1.
Determination of plasma pyruvate kinase activity.
Plasma pyruvate kinase activity was determined by the method of Gutmann and Bernt (36
), by use of a system coupled with lactate dehydrogenase and NADH. Plasma was added in 0.1 mol/L triethanolamine (pH 7.5) containing 0.15 mmol/L NADH, 1 mmol/L phosphoenolpyruvic acid, 4 mg/L lactate dehydrogenase and 3 mmol/L ADP. The reduction of NADH was measured spectrophotometrically at 340 nm for 5 min at 37°C using the molar absorption coefficient for NADH. A unit of pyruvate kinase activity was equivalent to the activity needed to catalyze the reaction of 1 µmol of ADP to ATP for 1 min.
Determination of tocopherol and tocotrienol concentrations.
Tocopherol and tocotrienol in the tissues and plasma were extracted as described previously (37
). Liver, kidney, heart, lung, brain, muscle and adipose tissue were homogenized in distilled water. Skin was ground under liquid nitrogen and then homogenized in distilled water. The tissue homogenate (0.5 mL) was put in a test tube, and 0.5 mL of ethanol containing 60 g/L pyrogallol and 0.45 µg of 2,2,5,7,8-pentamethyl-6-chroman as an internal standard were added. Then, 0.1 mL of 600 g/L potassium hydroxide was added and saponified at 70°C for 30 min. After the addition of 2.25 mL of 20 g/L sodium chloride, tocopherols and tocotrienols were extracted with 0.5 mL of hexane containing 10% (v/v) ethylacetate. Plasma (75 µL) was put in a test tube, and 90 ng of 2,2,5,7,8-pentamethyl-6-chroman as an internal standard was added. After the addition of 0.5 mL of water and 1.0 mL of ethanol, tocopherols and tocotrienols were extracted with 5 mL of hexane.
Concentrations of tocopherols and tocotrienols were determined by HPLC (38
). The instrumentation used for HPLC was a Shimadzu LC-10AS (Shimadzu, Kyoto, Japan) with a Shimadzu RF-10AXL fluorescence detector (excitation 298 nm, emission 325 nm). The analytical column used was a Develosil 60-5 (4.6 x 250 mm; Nomura Chemical, Aichi, Japan). The mobile phase was hexane containing 1% (v/v) dioxane and 0.2% (v/v) isopropyl alcohol with a flow rate of 1 mL/min.
Determination of urinary amounts of - and -CEHC.
Both conjugated and unconjugated - and -CEHC in the urine were methylated and extracted by the method of Kiyose et al. (39
). Water (60 mL) was added to lyophilized urine collected for 24 h, and 0.5 mL of the urine sample was added to 0.1 mL of 500 g/L ascorbic acid and 1 mL of 0.54 mmol/L EDTA. The urine sample was methylated in 3 mol/L methanolic hydrochloric acid at 60°C for 1 h under nitrogen, and the methylated tocopherol metabolite was extracted with hexane. The hexane was evaporated by nitrogen, and the residue was dissolved in 100 µL of 45% (v/v) acetonitrile containing 50 mmol/L sodium perchlorate; 10 µL of this solution was subjected to HPLC. The instrumentation used for HPLC was a Shimadzu LC-10AS, with a Coulochem II electrochemical detector (MC Medical, Osaka, Japan) and an ODS-3 column (2.1 x 250 mm; GL Science, Tokyo, Japan). The mobile phase was 45% (v/v) acetonitrile containing 50 mmol/L sodium perchlorate, pH 3.6, and the flow rate was 0.2 mL/min. For coulometric detection, the analytical and guard cells were set to +0.4 and +0.45 V, respectively.
Determination of TBARS concentrations.
TBARS concentration in the tissue was determined by the method of Ohkawa et al. (40
). Muscle and adipose tissue were homogenized in 11.5 g/L potassium chloride. Skin was ground under liquid nitrogen and then homogenized in 11.5 g/L potassium chloride. The tissue homogenate (0.3 mL) was put in a test tube, and 0.2 mL of 80 g/L SDS, 1.5 mL of 20% (v/v) acetic acid and 1.5 mL of 8 g/L thiobarbituric acid were added. After boiling for 1 h, TBARS was extracted with 5 mL of butanol containing 62.5 g/L pyridine, and the color developed was measured with spectrophotometer UV-1600 (Shimadzu) at 532 nm. The TBARS concentration is presented as nmol malondialdehyde (MDA), using MDA as an external standard.
Statistical analysis.
Data are presented as means ± SEM, n = 6. They were analyzed by one-way ANOVA with Fisher’s post hoc test. Differences were regarded as significant at P < 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Dietary vitamin E did not affect the food intake, growth or liver weight of the rats (Table 2
). The plasma pyruvate kinase activity (a marker of vitamin E deficiency) of the -Toc, -Toc3 and -Toc3 + -Toc groups was lower (P < 0.05) than that of the deficient group. The -tocopherol concentrations in the tissues and plasma of the -Toc and -Toc3 + -Toc groups were higher (P < 0.05) than those of the deficient and -Toc3 groups (Fig. 1
). -Tocotrienol was detected in all tissues and plasma of the -Toc3 group, and the concentrations in the heart, epididymal fat and skin were >10 nmol/g. The -tocotrienol concentrations in the liver, kidney, heart, lung, brain, muscle and plasma of the -Toc3 group were much lower (P < 0.05) than the -tocopherol concentrations in those tissues and plasma of the -Toc group. However, the -tocotrienol concentration in the perirenal adipose tissue, epididymal fat and skin of the -Toc3 group was higher (P < 0.05) than the -tocopherol level in the -Toc group. The -tocotrienol concentrations in the tissues and plasma of the -Toc3 + -Toc group were lower (P < 0.05) than those of the -Toc3 group. The urinary amounts of -CEHC in the -Toc and -Toc3 groups did not differ (P 0.05), and that of the -Toc3 + -Toc group was greater (P < 0.05) than those of the -Toc and -Toc3 groups (Fig. 2
). The urinary excretion of -CEHC was extremely low in all groups. The TBARS concentrations in the heart, muscle, perirenal adipose tissue and epididymal fat of the -Toc and -Toc3 groups were lower (P < 0.05) than those of the deficient group (Fig. 3
). In the heart and adipose tissues, the TBARS concentrations of the -Toc and -Toc3 groups did not differ (P 0.05). The TBARS concentration in the skin of all groups did not differ (P 0.05) (data not shown).
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Dietary vitamin E did not affect the food intake, growth or liver weight of the rats (Table 2)
. The plasma pyruvate kinase activity of the -Toc3 group was higher (P < 0.05) than that of the -Toc and -Toc3 + -Toc groups. The -tocopherol concentrations in the adipose tissue and skin (Fig. 4
) and the liver, kidney, heart, lung, brain, muscle and plasma of the -Toc and -Toc3 + -Toc groups were much higher (P < 0.05) than those of the -Toc3 group fed a -Toc–free diet, whereas those of the -Toc and -Toc3 + -Toc groups did not differ (P 0.05). -Tocotrienol preferentially accumulated in the adipose tissue and skin (Fig. 4)
. The -tocotrienol concentrations were either not detected in the brain and plasma or were <1.4 nmol/g in the liver, kidney, heart, lung and muscle. In the perirenal adipose tissue, the -tocotrienol concentration of the -Toc3 group and the -tocopherol concentration of the -Toc group did not differ (P 0.05), although the -tocotrienol concentrations in the epididymal fat and skin of the -Toc3 group were lower (P < 0.05) than the -tocopherol concentrations in those tissues of the -Toc group. In the perirenal adipose tissue, epididymal fat and skin, the -tocotrienol concentrations of the -Toc3 and -Toc3 + -Toc groups did not differ (P 0.05). The urinary excretions of -CEHC by the -Toc and -Toc3 + -Toc groups did not differ (P 0.05) (Fig. 5
). Urinary excretions of -CEHC by the -Toc3 and -Toc3 + -Toc groups were much greater (P < 0.05) than that of the -Toc group, whereas excretions of -CEHC by the -Toc3 and -Toc3 + -Toc groups did not differ (P 0.05). The TBARS concentration in the perirenal adipose tissue of the -Toc3 group was higher (P < 0.05) than that of the -Toc group, whereas that of the -Toc3 + -Toc group was the lowest (P < 0.05) of all groups (Fig. 6
).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
- and -tocotrienols preferentially accumulate in the adipose tissue and skin of rats and mice fed a diet containing TRF, a mixture of -tocopherol and - and -tocotrienols (32
,33
). We studied the distribution of dietary - or -tocotrienol in rats fed a diet containing - or -tocotrienol alone. Dietary -tocotrienol was detected in all tissues and plasma of the rats fed a diet containing -tocotrienol for 8 wk (Fig. 1)
. In adipose tissue and skin, the -tocotrienol concentration of the rats fed -tocotrienol alone was greater than the -tocopherol concentration of the rats fed -tocopherol alone. Dietary -tocotrienol accumulated in the adipose tissue and skin (Fig. 4)
, but little was detected in the other tissues and plasma of the rats fed -tocotrienol. Our results indicated that the adipose tissue and skin of the rats fed tocotrienol are rich in tocotrienol. We have previously shown that -tocotrienol was undetected or detected in only negligible amounts in various tissues (except for adipose tissue and skin) and in the plasma of rats fed TRF (33
). Thus -tocopherol decreases the -tocotrienol concentrations in the tissues and plasma of rats.
Patients who have ataxia with vitamin E deficiency also have an extremely low plasma vitamin E concentration because of mutations in the -TTP gene (41
). The results showed that the affinity for -TTP is a critical determinant of the distribution of tocopherol and tocotrienol. The relative affinity of -tocotrienol for -TTP is 12% that of -tocopherol (42
). The -tocotrienol concentrations in the liver, kidney, heart, lung, brain muscle and plasma of the rats fed -tocotrienol alone were much lower than the -tocopherol concentrations in those tissues and plasma of the rats fed -tocopherol alone (Fig. 1)
because of the low affinity of -tocotrienol for -TTP. However, the low affinity for -TTP could not explain the result that the -tocotrienol concentrations in the adipose tissues and skin of the rats fed -tocotrienol alone were greater than the -tocopherol concentrations in those tissues of the rats fed -tocopherol. Moreover, -tocotrienol preferentially accumulated in the adipose tissues and skin (Fig. 4)
. The precise mechanism of the accumulation of tocotrienol in the adipose tissues and skin is unknown. The presence of an -TTP–independent vitamin E transport pathway has been suggested (18
,43
). Lipoprotein lipase (EC 3.1.1.34) has the transfer activity of vitamin E in vitro (44
) and in vivo (45
). Tocopherol and tocotrienol may be transferred from chylomicrons to some tissues by lipoprotein lipase before discrimination by -TTP in the liver. The unsaturated phytyl tail of tocotrienol might enhance its transfer from chylomicrons to the tissues such as the adipose tissue or skin, and possibly modulate its stability in the lipid attributed to the fluidity of the phytyl tail. In their review, Blatt et al. (21
) indicate that an estimated 90% of total body vitamin E was in the adipose tissue in normal subjects. Brouwer et al. (46
) report that orally administered vitamin D, a fat-soluble vitamin, rapidly accumulated in the adipose tissue and that it was very slowly released. It is likely that the adipose tissue may act as a buffer to store the excess amount of fat-soluble vitamin and release it slowly under fasting conditions.
Recently, many reports have indicated that tocopherol and tocotrienol are metabolized to carboxychromans and excreted into urine in humans (23
–25
) and rats (39
,47
). Both -tocopherol and -tocotrienol are metabolized to -CEHC, and both -tocopherol and -tocotrienol are metabolized to -CEHC. In this study, the urinary excretion of - or -CEHC was determined in rats fed a diet containing 50 mg -tocopherol and - or -tocotrienol/kg diet for 8 wk. Urinary excretion of -CEHC, during the last 24 h of the experimental period, by rats fed a diet containing 50 mg -tocopherol/kg or 50 mg -tocotrienol/kg diet was 105 nmol (a mean value of expts. 1 and 2) or 94 nmol, respectively (Figs. 2
and 5)
, whereas the urinary excretion of -CEHC by rats fed a diet containing 50 mg -tocotrienol/kg was 300 nmol (Fig. 5)
. The urinary excretion of each tocopherol or tocotrienol metabolite in the rats was estimated as follows: -tocopherol, 
26%; -tocotrienol, 24%; -tocotrienol, 75% of the dietary intake of tocopherol or tocotrienol because the daily intake of tocopherol or tocotrienol was 400 nmol/d. -Tocotrienol rather than -tocopherol or -tocotrienol may be preferentially metabolized in rats.
We studied the effect of dietary -tocopherol on the - or -tocotrienol concentration in rats fed a diet containing - or -tocotrienol with -tocopherol for 8 wk. Although -tocopherol lowered the -tocotrienol concentrations in tissues and plasma (Fig. 1)
, it affected neither the -tocotrienol concentrations in adipose tissue and skin (Fig. 4)
nor the urinary excretion of -CEHC, a metabolite of -tocotrienol (Fig. 5)
. Our results indicated that -tocopherol enhances the -tocotrienol but not the -tocotrienol metabolism. As mentioned above, the relative affinity of -tocotrienol for -TTP is 12% that of -tocopherol (42
). A small amount of -tocotrienol bound to -TTP in the liver and was transferred to the various tissues of the rats fed -tocotrienol without -tocopherol, so that the low levels of -tocotrienol were detected in the various tissues and plasma (Fig. 1)
. In the rats fed -tocotrienol with -tocopherol, a small amount of -tocotrienol may bind to -TTP because -tocopherol may preferentially bind to -TTP and be transferred to the various tissues. Thus, the low affinity of -tocotrienol for -TTP may lead to the lowering of the -tocotrienol concentrations by the dietary -tocopherol. However, a small amount of -tocotrienol was detected in the tissues (except the adipose tissue and skin) and plasma of the rats fed -tocotrienol without -tocopherol, and the urinary excretion of the -tocotrienol metabolite was greater than that of -tocopherol or -tocotrienol. The result suggests that the relative affinity of -tocotrienol for -TTP is much lower than that of -tocotrienol. The - or -tocotrienol that accumulated in the adipose tissue and skin of the rats fed - or -tocotrienol with -tocopherol may have been taken up into these tissues before the discrimination of -TTP in the liver.
However, dietary -tocopherol lowered the -tocopherol concentration in rats fed -tocopherol with -tocopherol (34
). Kiyose et al. (39
) report that -tocopherol increases the urinary excretion of -CEHC in rats orally administered -tocopherol with or without -tocopherol. Thus, -tocopherol enhances the metabolism of both -tocotrienol and -tocopherol. The very limited ability of HepG2 cells, a well-differentiated human hepatoblastoma line, to metabolize -tocopherol compared with -tocopherol has been reported (26
,27
,48
). Sontag and Parker (29
) have recently suggested that the preferential physiological retention of -tocopherol and the elimination of -tocopherol are explained in part by the catalytic activity of tocopherol--hydroxylase (CYP4F2). Their binding and catalytic affinity for tocotrienol and -tocopherol may account for the different effect of -tocopherol on - and -tocotrienol metabolism, although it remains unclear whether the same CYP isoform catalyzes both tocopherol and tocotrienol oxidation.
We studied the effect of tocotrienol in the tissues on TBARS concentrations because the antioxidative activity of -tocotrienol to inhibit lipid peroxidation in vitro was higher than that of -tocopherol (1
–3
). Dietary -tocotrienol decreased TBARS concentrations in the heart, muscle and adipose tissue (Fig. 3)
. Moreover, the plasma pyruvate kinase activity (a marker of vitamin E deficiency) of rats fed -tocotrienol was similar to that of rats fed -tocopherol, whereas that of rats fed -tocotrienol was higher than that of those fed -tocopherol (Table 2)
. These data may indicate that -tocotrienol, as well as -tocopherol, acts as a potent antioxidant in vivo. As mentioned earlier, several biological and physiological functions of tocotrienol have been reported (4
). However, it has been thought that the bioavailability of tocotrienol is very low because of its low affinity for -TTP. The present study suggests that its estimated bioavailability is not so low in some tissues.
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FOOTNOTES |
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2 Present address: Department of Food and Nutritional Environment, Kinjo Gakuin University, Nagoya 463-8521, Japan.
4 Abbreviations used: -CEHC, 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxycroman; -TTP, -tocopherol transfer protein; -CEHC, 2,7,8-trimethyl-2(2'-carboxyethyl)-6-hydroxycroman; CYP, cytochrome P450; MDA, malondialdehyde; TBARS, thiobarbituric acid reactive substance; TRF, tocotrienol-rich fraction.
Manuscript received 2 September 2002. Initial review completed 27 September 2002. Revision accepted 23 October 2002.
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