Vitamin E kinetics in smokers and nonsmokers.

Does cigarette smoking increase vitamin E utilization in vivo? A trial was carried out in 6 smokers and 5 nonsmokers of comparable ages and serum lipids. Subjects consumed 75 mg each d(3)-RRR and d(6)-all rac-alpha-tocopheryl acetates (natural and synthetic vitamin E, respectively) daily for 7 d with a standardized breakfast. Fasting blood samples were drawn on days -7, -6, -5, -4, -3, -2, -1, 0, 1, 2, 3, 4, 5, 6, 7, 9, 14, 21 (negative days indicate supplementation). In both groups, plasma d(3)-alpha-tocopherol concentrations were approximately double of d(6)-alpha-tocopherol. At day 0, the %d(3) alpha-tocopherols (d(3)-alpha-tocopherol/total-alpha-tocopherol x 100) were similar in both smokers and nonsmokers. Subsequently, there was a trend toward a faster exponential disappearance of the plasma %d(3) alpha-tocopherol in smokers compared with nonsmokers (0.30 +/- 0.04 compared with 0.24 +/- 0.05, p =.0565). The calculated %d(3) half-lives were 55.6 +/- 7.4 h in smokers and 72.1 +/- 17.3 h in nonsmokers (p =.0630). By day 21, the %d(3) in smokers had decreased to 1.4% +/- 0.3% while it was 2.2% +/- 0.7% (p =.0418) in the nonsmokers. These data suggest that smoking increases plasma vitamin E disappearance, but further studies are needed to confirm this finding and to assess its cause.

Cystic fibrosis: nutritional status and micronutrients.

Recent studies have focused on the current dietary intake of cystic fibrosis patients, the impact of nutritional support on both the nutritional status and clinical outcome variables, and the effects on the nutritional status of antibiotic therapy and surgical treatment of meconium ileus. In addition to weight and height, skinfold measurements, bioelectrical impedance analysis and dual energy X-ray absorptiometry have been employed for the determination of nutritional status. A proton pump inhibitor has been used successfully along with pancreatic enzymes for the improvement of fat absorption. Attention has been paid to resting energy expenditure during pulmonary exacerbations, to vitamin K function in bone mineralization and to risk factors for low bone mineral density in cystic fibrosis. The relationships between glutathione and nutritional status have been studied, along with possible interactions with albumin, a potent antioxidant. Finally, a beneficial effect of docosahexaenoic acid on cystic fibrosis pathology has been suggested, but this requires further critical evaluation.

Effects of pancreatic enzyme preparations on erythrocyte glutathione peroxidase activities and plasma selenium concentrations in cystic fibrosis.

To substitute for exocrine pancreatic insufficiency, patients with cystic fibrosis (CF) take pancreatic enzymes (PE) originating from porcine pancreas. Five different pancreatic enzyme preparations used by our patients contained 0.5-1.4 microg selenium per g tablet. In patients taking PE in doses that were gradually increased to improve fat absorption during a 48-month period, the effects of PE dose on erythrocyte selenium-dependent glutathione peroxidase (SeGSH-Px) activities and plasma selenium concentrations were studied. At baseline, erythrocyte SeGSH-Px activities were significantly lower in patients (p=.01), while plasma selenium concentrations did not differ between patients and healthy subjects. When PE dose and, consequently, selenium intake from PE was increased, erythrocyte SeGSH-Px activities (p < .001) and plasma selenium concentrations (p=.02) increased. Changes in SeGSH-Px activities during the initial 8 months correlated with those in selenium intake from PE (r=0.67, p < .001). Plasma selenium concentrations plateaued at 12 months and erythrocyte SeGSH-Px activities did so at 36 months, when patients had reached SeGSH-Px activities similar to those of healthy subjects. At 48 months, patients took an average lipase dose of 17400 U x kg(-1) x d(-1) and selenium dose from PE of 0.53 microg x kg(-1) x d(-1). We conclude that selenium content of PE preparations has a significant effect on SeGSH-Px activity in patients with CF. This form of selenium supply needs to be taken into account when selenium supplements are given to patients with CF.

Plasma vitamin C concentrations in patients with cystic fibrosis: evidence of associations with lung inflammation.

Vitamin C status and possible associations with the disease process in cystic fibrosis (CF) patients were investigated. Plasma vitamin C concentrations in patients from two different mid-European populations (Swiss, n = 62; Austrian, n = 60) taking no or low-dose vitamin C from multivitamin supplements did not differ from each other or from control subjects (n = 34). Vitamin C concentrations decreased with age (5.05 mumol.L-1, y-1). When followed up for 12 mo, patients had the highest plasma vitamin C concentrations in February and the lowest in May and August (P < 0.01); the decrease in vitamin C was accompanied by increases in plasma malondialdehyde (P < 0.001) and tumor necrosis factor alpha concentrations (P < 0.01). During supplementation with vitamin E for 2 mo or beta-carotene for 12 mo vitamin C concentrations did not change. They correlated inversely with white blood cell count (r = -0.36, P = 0.008), bands (r = -0.36, P = 0.02), alpha 1-acid glycoprotein (r = -0.45, P = 0.002), interleukin 6 (r = -0.46, P = 0.0006), and neutrophil elastase/alpha 1-proteinase inhibitor complexes (r = -0.34, P = 0.02). In patients with vitamin C concentrations < 40 mumol/L, all indexes of inflammation were relatively high, whereas those with concentrations > 80 mumol/L (upper quartile of control subjects) showed clearly lower values. These results are consistent with the hypothesis that by scavenging oxygen free radicals vitamin C interacts with an inflammation-amplifying cycle of activation of alveolar macrophages and neutrophils, release of proinflammatory cytokines and oxygen free radicals, and inactivation of antiproteases.

Neutrophil elastase/alpha 1-proteinase inhibitor complex levels decrease in plasma of cystic fibrosis patients during long-term oral beta-carotene supplementation.

Lung inflammation in cystic fibrosis (CF) is associated with an increased release from activated neutrophils of oxidants and proteinases. Free radical generation is not efficiently neutralized, and the major anti-proteinase, alpha 1-proteinase inhibitor (alpha 1-PI) is thought to be oxidatively inactivated. We hypothesized that enhanced antioxidant protection could represent an additional long-term strategy to attentuate the host inflammatory response. The effect on plasma neutrophil elastase/alpha 1-PI (NE/alpha 1-PI) complex levels (as a marker of lung inflammation) and plasma malondialdehyde concentrations (as a marker of lipid peroxidation) of additional oral beta-carotene supplementation was studied in 33 CF patients who had already received long-term vitamin E supplementation. In the presence of a more than 10-fold increase in plasma beta-carotene concentrations (mean +/- SEM) (0.09 +/- 0.01 to 1.07 +/- 0.19 mumol/L; p < 0.0001), a small increase in plasma alpha-tocopherol concentrations (23.8 +/- 1.31 to 28.4 +/- 1.81 mumol/L; p = 0.02), and a more than 50% decrease in plasma malondialdehyde concentrations (1.00 +/- 0.07 to 0.46 +/- 0.03 mumol/L; p < 0.0001), plasma NE/alpha 1-PI complex levels decreased from 102.2 +/- 16.0 to 83.0 +/- 10.4 micrograms/L; (p = 0.02). Plasma retinol concentrations increased (1.05 +/- 0.06 to 1.23 +/- 0.07 mumol/L; p = 0.0001) due to conversion of beta-carotene to retinol, which could have contributed to the decrease in NE/alpha 1-PI complex levels. Based on these results, we speculate that efficient antioxidant supplementation could attenuate lung inflammation in CF.

Response to a single oral dose of all-rac-alpha-tocopheryl acetate in patients with cystic fibrosis and in healthy individuals.

Biochemical vitamin E deficiency and low plasma lipids are frequent findings in patients with cystic fibrosis (CF). The response to a single oral dose of all-rac-alpha-tocopheryl acetate [100 IU (100 mg)/kg body wt] was studied over 24 h in 25 CF patients with exocrine pancreatic insufficiency and in 23 healthy individuals. Patients received pancreatic enzymes together with the vitamin E test dose. At baseline, plasma alpha-tocopherol concentrations correlated with cholesterol concentrations; both were lower in patients than in control subjects, as were erythrocyte alpha-tocopherol concentrations (all P < 0.0001). Plasma and erythrocyte alpha-tocopherol concentrations were significantly higher than baseline concentrations from 3 and 6 h onward, respectively, and peaked most frequently at 6 and 12 h, respectively, in both patients and control subjects. Maximum increases and areas under the concentration time curves for plasma alpha-tocopherol concentrations were smaller in patients than in control subjects (P < 0.0001). When ratios of plasma alpha-tocopherol to cholesterol (to correct for differences in cholesterol concentrations) or erythrocyte alpha-tocopherol concentrations were applied, patients were shown to respond as efficiently as control subjects. On the basis of these results, we recommend vitamin E supplements in doses high enough to achieve vitamin E status in CF patients well within the range of healthy individuals; these supplements should be given with appropriate amounts of pancreatic enzymes. However, for long-term supplementation much lower doses than those used in this test situation may be sufficient.

Long-term oral vitamin E supplementation in cystic fibrosis patients: RRR-alpha-tocopherol compared with all-rac-alpha-tocopheryl acetate preparations.

To investigate the efficacy of three different vitamin E preparations for optimizing vitamin E status in cystic fibrosis (CF patients long-term, 29 patients (aged 0.7-29.8 y) were randomly assigned to receive 400 IU of either RRR-alpha-tocopherol (A: 268 mg, n = 10) or all rac-alpha-tocopheryl acetate as a fat-soluble (B: 400 mg, n = 10) or water-miscible preparation (C: 400 mg, n = 9) and were followed for 6 wk. In the whole study group, plasma alpha-tocopherol concentrations increased from baseline (10.5 +/- 4.6 micromol/L) to 3 wk (25.7 +/- 6.5 micromol/L; P < 0.001), but not further between 3 and 6 wk; concentrations at 3 and 6 wk did not differ from those of age-matched control subjects (23.6 +/- 3.9 micromol/L). There was no significant difference in the increase from baseline to 6 wk among preparations A (17.75 +/- 8.43 micromol/L), B (14.0 +/- 9.4 micromol/L), and C (15.5 +/- 7.1 micromol/L). Because of differences in body weight, the dose administered ranged from 5.5 to 47.4 IU x kg-1 x d-1; it correlated positively with the increase in plasma alpha-tocopherol concentrations (P < 0.001). There was no significant difference in the increase in plasma alpha-tocopherol concentrations between patients with CF-associated liver disease (n = 8) who received 10.2 +/- 3.8 IU x kg-1 x d-1 and those without liver disease taking comparable doses. We conclude that CF patients can be efficiently supplemented with 400 IU/d of any one of the three vitamin E preparations and plasma values of healthy control subjects can be achieved.

Impaired resistance to oxidation of low density lipoprotein in cystic fibrosis: improvement during vitamin E supplementation.

Antioxidants such as vitamin E protect unsaturated fatty acids of LDL against oxidation. In the ex vivo model used, LDL was exposed to Cu2+ ions, a potent prooxidant capable of initiating the oxidation of LDL. The lag time, indicating the delay of conjugated diene formation in LDL due to antioxidant protection, was measured in 54 cystic fibrosis (CF) patients with plasma alpha-tocopherol levels below (Group A, n = 30) or above (Group B, n = 24) 15.9 mumol/L (mean - 2 SD of Swiss population). Patients were reevaluated after 2 months on 400 IU/d of oral RRR-alpha-tocopherol. In group A, alpha-tocopherol concentrations in LDL increased significantly from 3.2 +/- 1.6 mol/mol LDL to 8.2 +/- 2.8 mol/mol (P < 0.001) and lag times increased from 79 +/- 33 min to 126 +/- 48 min (P < 0.001), whereas in the vitamin E sufficient group B no further increase neither in LDL alpha-tocopherol concentrations or in lag times was observed. LDL oleic acid concentrations were higher, and linoleic acid concentrations were lower in patients than in controls. After efficient vitamin E supplementation, lag times were positively related to LDL alpha-tocopherol (P < 0.01) and negatively to LDL linoleic and arachidonic acid content (P < 0.001). The maximum rate of oxidation correlated positively with linoleic and arachidonic acid concentrations, as did the maximum conjugated diene absorbance. These results indicate that LDL resistance to oxidation is impaired in vitamin E deficient CF patients but can be normalized within 2 months when alpha-tocopherol is given in sufficient amounts. Linoleic and arachidonic acid content exhibit a major influence on the LDL resistance to oxidation.

Response to oral beta-carotene supplementation in patients with cystic fibrosis: a 16-month follow-up study.

The aim of this study was to determine the efficacy of long-term oral beta-carotene supplementation for correcting impaired beta-carotene status in cystic fibrosis patients. Thirty-five patients (2.3-30.5 years of age) with coefficients of fat absorption of 46-96% (median 88%) received beta-carotene 0.5 mg/kg daily and were followed over a 16-month treatment period. Baseline plasma beta-carotene concentrations in patients (mean +/- SD, 0.09 +/- 0.06 mumol/l) were significantly lower than those of age-matched controls (0.86 +/- 0.56 mumol/l) (p < 0.0001). Concentrations increased rapidly and reached a plateau at or before 3 weeks that was maintained throughout the study period. Values obtained at 3 weeks (0.89 +/- 0.64 mumol/l) were significantly higher (p < 0.0001) than those at baseline and did not differ from controls. Plasma retinol and alpha-tocopherol concentrations increased during the observation period, but remained within normal ranges. Plasma retinyl palmitate, which was below the detection limit in all but one patient at baseline, did not increase. Thus oral beta-carotene supplementation is effective and normalizes beta-carotene status of cystic fibrosis patients without evidence of significant side effects.

Enhanced resistance to oxidation of low density lipoproteins and decreased lipid peroxide formation during beta-carotene supplementation in cystic fibrosis.

We investigated the effect of correcting beta-carotene deficiency in cystic fibrosis (CF) patients on two parameters of lipid peroxidation. The resistance to oxidation of low density lipoprotein (LDL) was measured by the lag time preceding the onset of conjugated diene formation during exposure to copper(II) ions, and lipid peroxide formation was quantitated by malondialdehyde concentrations in plasma (TBA/HPLC method). Simultaneously, alpha-tocopherol and beta-carotene concentrations were determined in LDL and in plasma. Thirty-four CF patients were investigated before and after 3 months of oral beta-carotene supplementation. Beta-carotene concentrations increased (p < 0.0001) in plasma (mean +/- SD) (0.09 +/- 0.06 vs. 1.07 +/- 0.86 mumol/l) and in LDL (0.02 +/- 0.02 vs. 0.31 +/- 0.28 mol/mol), without significant changes in alpha-tocopherol, either in plasma (24.7 +/- 5.9 vs. 25.4 +/- 7.6) or in LDL (8.47 +/- 2.95 vs. 9.05 +/- 4.13). Lag times, being shorter (p < 0.05) in patients than in controls, increased from 48.5 +/- 21.3 to 69.1 +/- 27.9 min (p < 0.001) and plasma MDA concentrations, being greater (p < 0.0001) in patients than in controls, decreased from 0.95 +/- 0.32 to 0.61 +/- 0.15 mumol/l (p < 0.0001). At 3 months, lag times and MDA concentrations did not any longer differ between patients and controls. These data suggest that excess lipid peroxidation occurring in beta-carotene deficiency can be limited and normalized during efficient beta-carotene supplementation in CF patients.

Oxygen free radicals and antioxidants in cystic fibrosis: the concept of an oxidant-antioxidant imbalance.

Patients with cystic fibrosis frequently exhibit increased oxygen free radical generation from activated neutrophils due to chronic lung inflammation on the one hand and antioxidant deficiencies due to exocrine pancreatic insufficiency on the other, resulting in an oxidant-antioxidant imbalance in favor of the former. As a consequence, free radical attack on unsaturated fatty acids of lipid structures leading to lipid peroxidation and damaging effects on proteins may occur. In the lung, antiproteases are thought to be inactivated by oxygen free radicals released from inflammatory cells. In the cholestatic liver, bile acids may propagate lipid peroxidation. An efficient antioxidant supply is suggested to control tissue injury by restoring the oxidant-antioxidant balance. Mechanisms involved in the generation of oxygen free radicals are described and data on the antioxidant defense system in cystic fibrosis patients are presented, together with evidence of increased lipid peroxidation. Possible implications for disease processes are discussed as well as therapeutic concepts to reconstitute the oxidant-antioxidant balance.

Short-term changes in erythrocyte alpha-tocopherol content of vitamin E-deficient patients with cystic fibrosis.

Polyunsaturated fatty acids of biomembranes are a major target of lipid peroxidation. In vitamin E deficiency an efficient delivery of a high oral loading dose of all-rac-alpha-tocopheryl acetate to erythrocyte membranes could provide an early onset antioxidative effect. We investigated short-term changes in erythrocyte alpha-tocopherol after a single oral dose of 100 mg all-rac-alpha-tocopheryl acetate/kg in 10 vitamin E-deficient cystic fibrosis (CF) patients. Over 24 h, erythrocyte alpha-tocopherol increased 68% to 420% of preloading concentrations. With two exceptions, peak values were achieved 12 or 24 h after administration, which was 3-18 h later than peak plasma concentrations. Separate median-based curve estimates for the changes in erythrocyte alpha-tocopherol for five patients with and five without associated cholestatic liver disease were obtained. Cross-sectional test results revealed significantly lower erythrocyte alpha-tocopherol for the 9- and 24-h observations for patients with cholestatic liver disease compared with those without. Oral all-rac-alpha-tocopheryl acetate can be rapidly incorporated into erythrocyte membranes in vitamin E-deficient CF patients.