Dietary coenzyme Q10 and vitamin E alter the status of these compounds in rat tissues and mitochondria.

Vitamin E (VE) and coenzyme Q (CQ) are essential for maintaining functions and integrity of mitochondria, and high concentrations of these compounds are found in their inner membranes. This study was conducted to examine the interaction between exogenously administered CQ10 and VE in rats. Male Sprague-Dawley rats (12 mo old) were fed a basal diet (10 IU VE or 6.7 mg RRR-alpha-tocopherol equivalent) supplemented with either 0 or 500 mg CQ10, and 0, 100 or 1310 IU VE/kg diet for 14 or 28 d. Liver, spleen, heart, kidney, skeletal muscle, brain and serum were analyzed for the levels of CQ10, CQ9 and VE. CQ10 supplementation significantly (P: < 0.05) increased CQ10 concentration in the liver and spleen (total and mitochondria) and serum, but not in other organs. Interestingly, rats supplemented with CQ10 plus 100 IU VE/kg diet had significantly higher CQ10 levels in the liver and spleen, whereas those supplemented with CQ10 plus 1310 IU VE/kg diet had lower levels, compared with those supplemented with CQ10 alone. As expected, dietary VE increased VE content in all of the organs analyzed in a dose-dependent manner. However, rats fed the basal diet supplemented with CQ10 had significantly higher VE levels in liver (total and mitochondria) than those not receiving CQ10 supplementation. CQ9 levels were higher in the liver and spleen, lower in skeletal muscle and unaltered in brain, serum, heart and kidney of rats supplemented with CQ10 compared with the controls. These data provide direct evidence for an interactive effect between exogenously administered VE and CQ10 in terms of tissue uptake and retention, and for a sparing effect of CQ10 on VE. Data also suggest that dietary VE plays a key role in determining tissue retention of exogenous CQ10.

Relative bioavailabilities of natural and synthetic vitamin E formulations containing mixed tocopherols in human subjects.

There are several reports in the literature on the relative bioavailabilities of RRR (natural) vs. all-rac (synthetic) forms of vitamin E in humans and animal models but none on the bioavailability of alpha-tocopherol in mixed vitamin E formulations. In the present study we examined the bioavailability of alpha-tocopherol in a typical commercially available product containing mixed tocopherols. We also tested a formulation containing all-rac-alpha-tocopherol with mixed tocopherols for purposes of comparison along with straight RRR- and all-rac-alpha-tocopheryl acetate as reference products. Normal male subjects were given one of the four formulations of vitamin E (800 IU per day in softgel capsule form for 10 days): 1. All-rac-alpha-tocopheryl acetate, 2. RRR-alpha-tocopheryl acetate, 3. RRR-alpha-tocopherol with mixed tocopherols, and 4. all-rac-alpha-tocopherol with mixed tocopherols. Both serum alpha- and gamma-tocopherols were determined by HPLC at baseline, and at days 2, 4, 7 and 10. The values for alpha- at baseline and 10 days were 0.80, 0.80, 0.80 & 0.79 mg/dl and 1.67, 1.72, 1.76 & 1.62 mg/dl. The values for gamma- were 0.28, 0.29, 0.30 & 0.29 mg/dl and 0.11, 0.08, 0.10 & 0.10 mg/dl. Thus the data show that a) the bioavailability of RRR- and all-rac-alpha-tocopherols is not affected by other tocopherols, and b) both RRR- and all-rac-alpha-tocopherol (free or esterified) significantly suppress the serum gamma tocopherol to the same extent. Furthermore, since there was no difference in the serum values of alpha-tocopherol between RRR- and all-rac-vitamin E given the same dose as IUs, the data also support the currently accepted ratio of 1.36 for the biopotency of RRR- vs. all-rac-alpha-tocopheryl acetate.

Relative bioavailability of coenzyme Q10 formulations in human subjects.

The relative bioavailability of typical commercially available forms of coenzyme Q10 (CoQ10) was compared with that of Q-Gel, a new solubilized form of CoQ10, in human subjects in two separate trials. In the first, standard softgel capsules containing CoQ10 suspension in oil, powder-filled hardshell capsules and powder-based tablets were tested along with Q-Gel using a daily dosage of 120 mg for three weeks. The baseline plasma CoQ10 values were all very tight (0.50-0.52 microgram/mL) and after three weeks the values were 1.37, 1.63 and 1.60 micrograms/mL for the first three products and 3.31 micrograms/mL for Q-Gel. The relative bioavailability calculated using the areas under the plasma CoQ10 curve (AUC) were (micrograms/mL x time in days) 7.16 (100%), 8.97 (125%), 9.19 (128%) and for Q-Gel 22.86 (319%). The second trial, carried out to replicate the findings in the first, employed only two groups, namely the standard softgel capsules containing the suspension and Q-Gel, and the duration was extended to four weeks. Plasma CoQ10 values were: baseline 0.40 and 0.38 and after four weeks 1.26 and 2.80; the corresponding AUCs were: 8.33 (100%) and 22.75 (273%). Thus, the data from both the trials show that Q-Gel, the new solubilized form of CoQ10, is vastly superior to typical commercially available preparations of CoQ10. This means much lower doses of Q-Gel will be required to rapidly reach and maintain adequate blood CoQ10 values than with any of the other currently available products.

Uptake and distribution of carotenoids, retinol, and tocopherols in human colonic epithelial cells in vivo.

Studies suggest that micronutrients such as the tocopherols, retinol, and the carotenoids have a chemopreventive action against colonic carcinogenesis and that they may be essential for the functioning and structural integrity of the gastrointestinal epithelium. In this study, we have determined the concentrations of tocopherols, retinol, and the carotenoids in human colonic epithelial cells using a noninvasive procedure developed in this laboratory (G.P. Albaugh et al., Int. J. Cancer, 52: 347-350, 1992). In subjects on a normal diet, almost all of these micronutrients were restricted to cells in the density range of rho 1.065-1.090 and rho 1.090-1.110. The lighter fraction (rho 1.033-1.064), representing the most senescent subpopulation, retained these micronutrients only when the subjects were on diets rich in vegetables. Cells isolated from subjects on their usual diets gave the following values expressed as ng/10(7) cells: alpha-tocopherol, 93-151; gamma-tocopherol, 152-280; retinol, 12-20; lutein, 4-18; cryptoxanthin, not detected; lycopene, 0-17; alpha-carotene, 3-7; and beta-carotene, 6-9. Peak responses in specific micronutrients following 5 days on a high carotenoid diet showed a lag period of at least 5 days, corresponding to the turnover rates of the epithelium itself. The evidence suggests that uptake of these micronutrients by the colonic mucosa occurs in the deep cryptal zone where the actively proliferating cells extract the nutrients from the systemic circulation.

Ascorbic acid and gastrointestinal cancer.

A literature review was made to critically evaluate the ability of ascorbic acid to modulate the incidence of gastrointestinal cancer. A comparison of preclinical, clinical, and epidemiological studies indicated that evidence for ascorbic acid as an inhibitor of carcinogenesis is stronger with regard to gastric cancer and weaker with regard to esophageal and colon/rectal cancer. Insufficient evidence currently exists regarding the oral cavity and the use of ascorbic acid in precancerous conditions such as polyposis and leukoplakia.

Renal excretion of ascorbic acid: effect of age and sex.

To determine if the lower plasma ascorbic acid concentrations observed in males compared to females, and in the elderly in general, might be due to differences in renal clearances of ascorbic acid, tubular maximum reabsorptions (TmAA) and renal thresholds for ascorbic acid were determined on older (10 male, 10 female, aged 70-86 years) and younger (3 male, 5 female, aged 26-59 years) subjects. The mean TmAA for men was 1.54 +/- 0.29 and for women 1.39 +/- 0.33 mg/minute/100 mL glomerular filtration rate (p > 0.05). The mean renal threshold for men was 1.51 +/- 0.25 and for women 1.26 +/- 0.16 mg/dL (p < 0.02). Neither was affected by age. If differences in TmAA and renal threshold were to explain the lower plasma ascorbic acid concentrations observed in males, both values should have been lower than in females. The ability of women to maintain higher plasma ascorbic acid concentrations than men, and young higher than elderly, cannot be explained by differences in the renal handling of ascorbic acid.

Dietary fish oil-induced changes in the distribution of alpha-tocopherol, retinol, and beta-carotene in plasma, red blood cells, and platelets: modulation by vitamin E.

Healthy men (ages 24-57 y) were fed a controlled basal diet supplemented with 15 g/d of placebo oil (PO) for 10 wk followed by 15 g/d of fish-oil concentrate (FO) (fortified with 15 mg all-rac-tocopherol) for 10 wk without additional alpha-tocopherol and the last 8 wk with 200 mg alpha-tocopherol/d (FO+E). Compared with PO, FO raised plasma malondialdehyde; lowered alpha-tocopherol in plasma, red blood cells, and platelets; and raised plasma and platelet beta-carotene. Supplementation with additional alpha-tocopherol (FO+E) not only restored tocopherol concentrations but also reversed the rise in beta-carotene. The response in retinol, particularly in platelets, showed an inverse relationship to beta-carotene, alpha-tocopherol exhibiting a modulating effect on these changes. From these observations it is postulated that platelets may be a significant extraintestinal site of retinol formation from beta-carotene.

Uptake and bioconversion of alpha-tocopheryl acetate to alpha-tocopherol in skin of hairless mice.

The photoprotective effect of topically applied alpha-tocopheryl acetate (vitamin E acetate), a stable derivative of alpha-tocopherol (vitamin E), and its possible bioconversion to the active antioxidant species (alpha-tocopherol) was examined in skin tissue of female hairless mice (HRS/J) exposed to UV-B irradiation. Our results indicate that topically applied alpha-tocopheryl acetate is absorbed into and retained by skin tissue. Furthermore, skin tissue from UV-B-irradiated animals that received daily topical alpha-tocopheryl acetate treatments contained significantly higher levels (P < 0.001) of alpha-tocopheryl acetate than non-UV-B-irradiated mice that received identical daily topical alpha-tocopheryl acetate treatments. Finally, free alpha-tocopherol levels in skin also were significantly increased (P < 0.001) by topical applications of alpha-tocopheryl acetate and skin levels of free alpha-tocopherol were significantly greater (P < 0.001) in UV-B-irradiated animals that received daily topical alpha-tocopheryl acetate treatments than in non-UV-B-irradiated animals. These results suggest that UV-B irradiation enhances both the absorption of alpha-tocopheryl acetate and its bioconversion to free alpha-tocopherol.

Correlation between the disintegration time and the bioavailability of vitamin C tablets.

The goal of this study was to examine if the current USP disintegration standard for vitamin C tablets (max. 30 min in water at 37 degrees C with disks) is adequate or if a tighter disintegration standard (e.g., European compendia max. 15 min) should be recommended based on bioavailability considerations. Four formulations of 500-mg vitamin C tablets ranging in mean disintegration time from 9 to 120 min were compared with a standard vitamin C solution in a double-blind clinical trial with 15 subjects. The products were administered with a standard breakfast. The data show that a solution of vitamin C and a fast-disintegrating tablet (8-9 min) have equal but significantly lower bioavailability than tablets with longer disintegration times (30, 60, 120 min). Tablets with a mean disintegration time of 60 min showed the highest bioavailability. When the disintegration test was performed without disks, disintegration times increased so much that only the tablets with the fastest disintegration time (which were also the tablets with the lowest bioavailability) met the current USP disintegration time limit. Based on the results of the study, changes in the USP standard to omit the disks or to shorten the disintegration time will not achieve enhanced bioavailability but will result in reduced vitamin C absorption. In vitro dissolution of vitamin C tablets did not show the traditional relationship with bioavailability.

Relationship between serum lipid peroxidation products in hypercholesterolemic subjects and vitamin E status.

The relationship of serum lipid peroxidation products in hypercholesterolemic subjects to their vitamin E intake was examined in 15 such subjects with no other associated significant disease process in a 3 month trial with vitamin E supplementation. These patients with elevated serum cholesterol levels also have elevated thiobarbituric acid reactive substances (TBARS) and lipid oxidation products (LOPS). Vitamin E supplementation of 800 IU daily normalized the lipid peroxidation products but did not significantly change serum lipids.

Vitamin E supplementation, plasma lipids and incidence of restenosis after percutaneous transluminal coronary angioplasty (PTCA).

To test whether alpha-tocopherol prevents restenosis following percutaneous transluminal coronary angioplasty (PTCA), we enrolled patients in a double-blind, placebo-controlled trial. Patients were randomized after successful PTCA to receive vitamin E in the form of dl-alpha-tocopherol, 1200 IU/day, orally vs an inactive placebo for 4 months. Patients' blood was analyzed at baseline and at 4 months post-PTCA for differences in plasma lipids, lipoproteins, apolipoproteins, alpha-tocopherol, retinol, beta-carotene and lipoperoxide concentrations. One hundred patients completed the protocol. No significant difference was found in any parameter except alpha-tocopherol level between the vitamin E group and the placebo group, verifying compliance. Follow-up cardiac catheterization was obtained in 83% of the patients receiving placebo and in 86% of the patients receiving dl-alpha-tocopherol. Including thallium and exercise stress testing, objective information was obtained for practically all the patients receiving dl-alpha-tocopherol or placebo. Restenosis was defined as the presence of a lesion with greater than or equal to 50% stenosis in a previously dilated artery segment and results were analyzed with respect to pre- and post-PTCA artery diameter, vessel diameter at follow-up, and restenosis rate. Patients receiving dl-alpha-tocopherol had a 35.5% restenosis angiographically documented vs 47.5% restenosis in patients receiving the placebo. The overall incidence of restenosis defined by an abnormal angiogram or thallium test or exercise stress test was 34.6% in patients receiving dl-alpha-tocopherol and 50% in patients receiving the placebo. This difference (p = 0.06) did not reach significance because of an inadequate sample size.

A longitudinal study of the relationship between vitamin A supplementation and plasma retinol, retinyl esters, and liver enzyme activities in a healthy elderly population.

This study examined the association between dietary supplementation with vitamin A and biochemical symptoms of toxicity in 116 healthy elderly volunteers (47 male, 69 female), aged 64-88 y. Plasma retinol and retinyl ester concentrations, seven liver-function tests, and dietary and supplemental vitamin A intakes were measured annually for 5 y. Supplemental intake range was 0-47,000 IU/d; dietary intake range was 2528-23,032 IU/d. Fasting retinol and retinyl ester concentrations were determined by HPLC and dietary intake was assessed by a 3-d food record. Supplemental vitamin A intake was highly correlated with retinyl ester concentrations (r = 0.74, P = 0.0001). Retinyl esters ranges from 3.4% to 10.2% of retinol concentrations. Retinyl ester concentrations did not increase over time, regardless of supplement amount. The association of retinyl esters and liver-function tests was significant only for aspartate aminotransferase activity in females (r = 0.47, P = 0.0001). The supplementation amount in this study was not associated with vitamin A toxicity.

Increased vitamin E intake restores fish-oil-induced suppressed blastogenesis of mitogen-stimulated T lymphocytes.

We sought to determine whether fish-oil supplementation would suppress blastogenesis in vitro of concanavalin A (ConA)-stimulated peripheral blood mononuclear cells (PBMCs) and, if so, whether it could be reversed with increased intake of vitamin E. Healthy males ate a controlled basal diet providing a total of 40% of energy from fat when fed in conjunction with 15 g/d of either placebo oil (PO) or fish-oil concentrate (FOC) fortified with 15 mg alpha-tocopherol/d for three periods. The subjects were supplemented with PO for 10 wk (PO), with FOC for 10 wk (FOC), and with FOC plus an additional 200 mg alpha-tocopherol/d for 8 wk (FOC+E). During FOC supplementation mitogenic responsiveness of PBMCs to ConA was suppressed, but this effect was reversed by concurrent supplementation with all-rac-alpha-tocopherol (FOC+E). There was a significant positive relationship (P less than 0.001) between plasma alpha-tocopherol concentrations and responsiveness of T lymphocytes to ConA.

Effects of omega 3 fatty acids and vitamin E on hormones involved in carbohydrate and lipid metabolism in men.

Forty healthy men were fed diets providing 40% of energy from fat and a minimum of 25 mg vitamin E for 28 wk. During the first 10 wk diets were supplemented with placebo, 15 g mixed fat/d. During the second 10 wk placebo was replaced by 15 g fish-oil concentrate/d. During the last 8 wk 200 mg vitamin E/d was added to fish oil. Compared with placebo, fish-oil feeding significantly increased plasma glucose and decreased triacylglycerol, insulin, glucagon, growth hormone, and somatomedin C. The changes in plasma cholesterol, cortisol, and dehydroepiandrosterone sulphate (DHEA-S) were not significant. Fish oil plus vitamin E further decreased insulin, growth hormone, and DHEA-S and reversed the effect of fish-oil on somatomedin C. The changes in glucose, glucagon, growth hormone, and cortisol were not significant. Thus, changes in plasma glucose and lipids caused by dietary fish oil alone and with fish oil plus vitamin E appear to be due to alterations in hormones involved in carbohydrate and lipid metabolism.

A randomized trial of replacement antioxidant vitamin therapy for neutrophil locomotory dysfunction in blunt trauma.

Studies in patients with serious trauma indicate that the observed neutrophil (PMN) locomotory dysfunction is partly the result of auto-oxidation as shown by evidence of preactivation, diminished reducing capacity, and low serum and cellular ascorbic acid and alpha-tocopherol. To investigate whether replacement of the antioxidant vitamins ascorbic acid and alpha-tocopherol can improve the PMN locomotory defect, ascorbic acid, alpha-tocopherol, ascorbic acid and alpha-tocopherol, or placebo was administered to a total of 46 victims of blunt trauma. PMN locomotion was quantitated using a micropore filter assay. Locomotion data were analyzed by repeated measures analysis with a split plot design and data for days 2-6 after injury were compared. Compared with placebo, the antioxidants improved PMN locomotion. The mean differences in distance migrated (treated minus placebo) were ascorbic acid and alpha-tocopherol = 11.3 +/- 3.0 microns (one-tailed p = 0.001) (mean +/- SE); ascorbic acid = 4.7 +/- 3.4 microns (p = 0.19); and alpha-tocopherol = 3.3 +/- 2.9 microns (p = 0.27). Although both antioxidants given together produced the best results, a plot of the 95% confidence intervals indicates that ascorbic acid and alpha-tocopherol, either given alone, were also better than placebo. We conclude that antioxidant replacement therapy significantly improves the PMN locomotory abnormality in blunt trauma.

Ascorbate and dehydroascorbate: distribution in mononuclear cells of healthy elderly people.

Concentrations of ascorbic acid and total ascorbate (ascorbic acid + dehydroascorbic acid) were determined in mononuclear cells from eight elderly men and nine elderly women (aged greater than 65 y) on controlled intakes of vitamin C. No increase in mononuclear cell ascorbic acid concentration was observed for intakes between 30 and 280 mg/d. A significant increase in total ascorbate concentrations was observed for the same range of intakes (p less than 0.01), primarily because of an increase in dehydroascorbic acid. Women were found to have significantly higher ascorbic acid concentrations in mononuclear cells than men (p less than 0.02) for similar intakes of vitamin C. No difference was observed for total ascorbate concentrations. The ratio of dehydroascorbate to ascorbate increased with increasing intake of vitamin C for both men and women.

Ascorbic acid intake and plasma levels in healthy elderly people.

Plasma ascorbic acid concentrations were determined in eight men and nine women over age 65 on controlled intakes of vitamin C. Plasma ascorbic acid levels were significantly lower in elderly men compared with women for vitamin C intakes ranging from 30 to 280 mg/d. A maximum steady-state level of 1.0 mg/dL (56.78 mumol/L) ascorbic acid was observed in male subjects at an intake of approximately 150 mg/d; female subjects approached a plasma ascorbate level of 1.0 mg/dL (56.78 mumol/L) with an intake of approximately 80 mg/d. At a total vitamin C intake of 60 mg/d, plasma ascorbate levels in men were estimated to be 0.4 mg/dL (22.71 mumol/L) or less. The amount of dehydroascorbic acid in plasma did not vary with intake of vitamin C.

Comparison of plasma alpha and gamma tocopherol levels following chronic oral administration of either all-rac-alpha-tocopheryl acetate or RRR-alpha-tocopheryl acetate in normal adult male subjects.

Vitamin E was administered orally (400 IU twice a day) to adult male humans for 28 days as either dl-alpha-tocopheryl acetate (all-rac-alpha-tocopheryl acetate) or d-alpha-tocopheryl acetate (RRR-alpha-tocopheryl acetate). Plasma alpha-tocopherol rose rapidly and fell at the same rate following cessation of supplementation with both forms of vitamin E. No significant differences in plasma alpha- or gamma-tocopherol levels were found between the two forms of vitamin E following their administration. The results confirm the currently accepted biopotencies of 1.0 IU/mg and 1.36 IU/mg, respectively for the two forms of vitamin E. Supplementation with either form of alpha-tocopheryl acetate resulted in depressing plasma gamma-tocopherol to less than 1/3 of initial levels; also the gamma/alpha ratio was depressed to less than 1/7 of the initial value. The study suggests that the gamma/alpha vitamin E ratio might also serve as a sensitive index of alpha-tocopherol ingestion.

A double blind study of vitamin B6 in Down's syndrome infants. Part 1--Clinical and biochemical results.

Nineteen patients with Down's syndrome participated in a double blind study of the clinical effects of pharmacological doses of vitamin B6 administration, starting under 8 weeks of age and continuing until 3 years of age. Ten patients received the vitamin and nine the placebo. In Part 1 of this study, no statistically significant differences were found between the two groups in mental age, height, weight, cranial circumference or tongue protrusion. A study of side effects conducted on a larger open population found vitamin B6 to be relatively safe when administered over long periods of time with photosensitive blisters as the major complication.