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BackgroundNumerous abnormalities in cystic fibrosis (CF) could influence tocopherol absorption, transportation, storage, metabolism and excretion. We hypothesized that the oxidative distress due to inflammation in CF increases vitamin E utilization, which could be positively influenced by supplemental vitamin C administration.MethodsImmediately before and after receiving vitamin C (500 mg) twice daily for 3.5 weeks, adult CF patients (n = 6) with moderately advanced respiratory tract (RT) disease consumed a standardized breakfast with 30% fat and a capsule containing 50 mg each hexadeuterium (d6)-α- and dideuterium (d2)-γ-tocopheryl acetates. Blood samples were taken frequently up to 72 h; plasma tocopherol pharmacokinetics were determined. During both trials, d6-α- and d2-γ-tocopherols were similarly absorbed and reached similar maximal plasma concentrations ~18-20 h. As predicted, during vitamin C supplementation, the rates of plasma d6-α-tocopherol decline were significantly slower.ConclusionsThe vitamin C-induced decrease in the plasma disappearance rate of α-tocopherol suggests that vitamin C recycled α-tocopherol, thereby augmenting its concentrations. We conclude that some attention should be paid to plasma ascorbic acid concentrations in CF patients, particularly to those individuals with more advanced RT inflammatory disease and including those with severe exacerbations.

Muscle wasting occurs with aging and may be a result of oxidative stress damage and potentially inadequate protection by lipophilic antioxidants, such as vitamin E. Previous studies have shown muscular abnormalities and behavioral defects in vitamin E-deficient adult zebrafish. To test the hypothesis that there is an interaction between muscle degeneration caused by aging and oxidative damage caused by vitamin E deficiency, we evaluated long-term vitamin E deficiency in the skeletal muscle of aging zebrafish using metabolomics. Zebrafish (55 days old) were fed E+ and E− diets for 12 or 18 months. Then, skeletal muscle samples were analyzed using UPLC-MS/MS. Data were analyzed to highlight metabolite and pathway changes seen with either aging or vitamin E status or both. We found that aging altered purines, various amino acids, and DHA-containing phospholipids. Vitamin E deficiency at 18 months was associated with changes in amino acid metabolism, specifically tryptophan pathways, systemic changes in the regulation of purine metabolism, and DHA-containing phospholipids. In sum, while both aging and induced vitamin E deficiency did have some overlap in altered and potentially dysregulated metabolic pathways, each factor also presented unique alterations, which require further study with more confirmatory approaches. [ABSTRACT FROM AUTHOR]

Although vitamin E acetate (VEA) is suspected to play a causal role in the development of electronic-cigarette, or vaping, product use-associated lung injury (EVALI), the underlying biological mechanisms of pulmonary injury are yet to be determined. In addition, no study has replicated the systemic inflammation observed in humans in a murine EVALI model, nor investigated potential additive toxicity of viral infection in the setting of exposure to vaping products. To identify the mechanisms driving VEA-related lung injury and test the hypothesis that viral infection causes additive lung injury in the presence of aerosolized VEA, we exposed mice to aerosolized VEA for extended times, followed by influenza infection in some experiments. We used mass spectrometry to evaluate the composition of aerosolized VEA condensate and the VEA deposition in murine or human alveolar macrophages. Extended vaping for 28 days versus 15 days did not worsen lung injury but caused systemic inflammation in the murine EVALI model. Vaping plus influenza increased lung water compared with virus alone. Murine alveolar macrophages exposed to vaped VEA hydrolyzed the VEA to vitamin E with evidence of oxidative stress in the alveolar space and systemic circulation. Aerosolized VEA also induced cell death and chemokine release and reduced efferocytotic function in human alveolar macrophages in vitro. These findings provide new insights into the biological mechanisms of VEA toxicity. [ABSTRACT FROM AUTHOR]

Although vitamin E acetate (VEA) is suspected to play a causal role in the development of electronic-cigarette, or vaping, product use-associated lung injury (EVALI), the underlying biological mechanisms of pulmonary injury are yet to be determined. In addition, no study has replicated the systemic inflammation observed in humans in a murine EVALI model, nor investigated potential additive toxicity of viral infection in the setting of exposure to vaping products. To identify the mechanisms driving VEA-related lung injury and test the hypothesis that viral infection causes additive lung injury in the presence of aerosolized VEA, we exposed mice to aerosolized VEA for extended times, followed by influenza infection in some experiments. We used mass spectrometry to evaluate the composition of aerosolized VEA condensate and the VEA deposition in murine or human alveolar macrophages. Extended vaping for 28 days versus 15 days did not worsen lung injury but caused systemic inflammation in the murine EVALI model. Vaping plus influenza increased lung water compared with virus alone. Murine alveolar macrophages exposed to vaped VEA hydrolyzed the VEA to vitamin E with evidence of oxidative stress in the alveolar space and systemic circulation. Aerosolized VEA also induced cell death and chemokine release and reduced efferocytotic function in human alveolar macrophages in vitro. These findings provide new insights into the biological mechanisms of VEA toxicity. [ABSTRACT FROM AUTHOR]

Background Human vitamin E (α-tocopherol) catabolism is a mechanism for regulating whole-body α-tocopherol. Objectives To determine the roles of the intestine and liver on α-tocopherol catabolism as affected by fat or fasting, 2 deuterium-labeled (intravenous d6- and oral d3-) forms of α-tocopherol were used. Methods Healthy women received intravenous d6-α-tocopherol and consumed d3-α-tocopherol with a 600-kcal defined liquid meal (DLM; 40% or 0% fat, n  = 10) followed by controlled meals; or the 0% fat DLM (n  = 7) followed by a 12-h fast (0% fat-fast), then controlled meals ≤72 h. The order of the 3-phase crossover design was not randomized and there was no blinding. Samples were analyzed by LC/MS to determine the α-tocopherol catabolites and α-carboxyethyl hydroxychromanol (α-CEHC) in urine, feces, and plasma that were catabolized from administered oral d3- and intravenous d6-α-tocopherols. Results Urinary and plasma d3- and d6-α-CEHC concentrations varied differently with the interventions. Mean ± SEM cumulative urinary d6-α-CEHC derived from the intravenous dose excreted over 72 h during the 40% fat (2.50 ± 0.37 μmol/g creatinine) and 0% fat (2.37 ± 0.37 μmol/g creatinine) interventions were similar, but a ∼50% decrease was observed during the 0% fat-fast (1.05 ± 0.39 μmol/g creatinine) intervention (compared with 0% fat, P  = 0.0005). Cumulative urinary d3-α-CEHC excretion was not significantly changed by any intervention. Total urinary and fecal excretion of catabolites accounted for <5% of each of the administered doses. Conclusions Differential catabolism of the intravenous d6-α-tocopherol and oral d3-α-tocopherol doses shows both liver and intestine have roles in α-tocopherol catabolism. During the 40% fat intervention, >90% of urinary d3-α-CEHC excretion was estimated to be liver-derived, whereas during fasting <50% was from the liver with the remainder from the intestine, suggesting that there was increased intestinal α-tocopherol catabolism while d3-α-tocopherol was retained in the intestine in the absence of adequate fat/food for α-tocopherol absorption. This trial was registered at clinicaltrials.gov as NCT00862433. [ABSTRACT FROM AUTHOR]

Background Determining the human vitamin E [α-tocopherol (α-T)] requirement is difficult, and novel approaches to assess α-T absorption and trafficking are needed. Objective We hypothesized that the dual-isotope technique, using 2 deuterium-labeled [intravenous (IV) d6- and oral d3-] α-T, would be effective in determining α-T fractional absorption. Further, defined liquid meal (DLM) fat or fasting would modulate α-T fractional absorption and lipoprotein transport. Methods A 3-phase cr ossover design was used. At 0 h, participants received IV d6-α-T and consumed d3-α-T with a 600-kcal DLM (40% or 0% fat) followed by controlled meals or by the 0% fat DLM, a 12-h fast, and then controlled meals. Blood samples and fecal samples were collected at intervals and analyzed by LC-MS. Pharmacokinetic parameters were calculated from plasma tracer concentrations and enrichments. Fractional absorption was calculated from d3- to d6-α-T areas under the curve, from a novel mathematical model, and from the balance method (oral d3-α-T minus fecal d3-α-T excreted). Results Estimated α-T fractional absorption during the 40% fat intervention was 55% ± 3% (mean ± SEM; n  = 10), which was 9% less than during the 0% fat intervention (64% ± 3%, n  = 10; P  < 0.02). Fasting had no apparent effect (56% ± 3%, n  = 7), except it slowed plasma oral d3-α-T appearance. Both balance data and model outcomes confirmed that the DLM fat did not potentiate d3-α-T absorption. During the IV emulsion clearance, HDL rapidly acquired d6-α-T (21 ± 2 nmol/L plasma per minute). During the first 8 h postdosing, triglyceride-rich lipoproteins (TRLs) were preferentially d3-α-T enriched relative to LDL or HDL, showing the TRL precursor role. Conclusions Quantitatively, α-T absorption is not limited by fat absence or by fasting. However, α-T leaves the intestine by a process that is prolonged during fasting and potentiated by eating, suggesting that α-T absorption is highly dependent on chylomicron assembly processes. This trial was registered at clinicaltrials.gov as NCT00862433. [ABSTRACT FROM AUTHOR]

Background: Inadequate vitamin E and magnesium intakes are of concern for older adults owing to the associated incidence of age-related diseases.Objective: This study was designed to determine the extent to which a 16-wk intervention with hazelnuts alters vitamin E and magnesium status in a group of older men and women, and used a pre-post intervention design without a control group to adjust for temporal changes.Methods: Participants (n = 32 including 22 women; mean ± SD age: 63 ± 6 y) consumed hazelnuts (∼57 g/d) for 16 wk. Blood and urine samples and anthropomorphic measures were taken at the start and end of the intervention to determine plasma concentrations of α-tocopherol and serum concentrations of magnesium, lipids, glucose, insulin, and high-sensitivity C-reactive protein along with urinary vitamin E metabolites; several other micronutrients were measured by a lymphocyte proliferation assay. There were 3 primary endpoints, calculated as the mean changes in measurements between baseline and the end of the 16-wk intervention for 1) plasma α-tocopherol, 2) urinary α-carboxyethyl hydroxychromanol (α-CEHC; an α-tocopherol metabolite), and 3) serum magnesium.Results: Hazelnut consumption increased concentrations of the urinary α-tocopherol metabolite α-CEHC (mean ± SD: 0.84 ± 0.45 to 1.14 ± 0.50 µmol/g creatinine; P = 0.0006). In addition, hazelnut consumption increased serum concentrations of magnesium (+2.1%, P = 0.05), decreased concentrations of fasting glucose (-3.4%, P = 0.03) and LDL cholesterol (-6.0%, P = 0.02), and decreased total:HDL cholesterol ratios (-4.5%, P = 0.009). No significant changes were observed in blood pressure, lymphocyte proliferation assays, and serum concentrations of insulin, high-sensitivity C-reactive protein, triglyceride, α-tocopherol, or HDL cholesterol.Conclusions: Consuming hazelnuts improves a biomarker of vitamin E status in older adults. Vitamin E is a shortfall micronutrient, as identified by the Dietary Guidelines for Americans 2015-2020, which frequently is consumed at levels less than the Estimated Average Requirement of 12 mg/d; thus, hazelnuts should be considered as part of a healthy dietary pattern. This trial was registered at clinicaltrials.gov as NCT03485989. [ABSTRACT FROM AUTHOR]

Background: Vitamin E supplementation improves liver histology in patients with nonalcoholic steatohepatitis, which is a manifestation of the metabolic syndrome (MetS). We reported previously that α-tocopherol bioavailability in healthy adults is higher than in those withMetS, thereby suggesting that the latter group has increased requirements. Objective: We hypothesized that α-tocopherol catabolites α-carboxyethyl hydroxychromanol (α-CEHC) and α-carboxymethylbutyl hydroxychromanol (α-CMBHC) are useful biomarkers of α-tocopherol status. Design: Adults (healthy or with MetS; n = 10/group) completed a double-blind, crossover clinical trial with four 72-h interventions during which they co-ingested 15 mg hexadeuterium-labeled RRR-α-tocopherol (d6-α-T) with nonfat, reduced-fat, whole, or soy milk. During each intervention, we measured α-CEHC and α-CMBHC excretions in three 8-h urine collections (0-24 h) and plasma α-tocopherol, α-CEHC, and α-CMBHC concentrations at various times ≤72 h. Results: During the first 24 h, participants with MetS compared with healthy adults excreted 41% less α-CEHC (all values are leastsquares means ± SEMs: 0.6 ± 0.1 compared with 1.0 ± 0.1 mmol/g creatinine, respectively; P = 0.002), 63% less hexadeuterium-labeled (d6)-α-CEHC (0.04 ± 0.02 compared with 0.13 ± 0.02 mmol/g creatinine, respectively; P = 0.002), and 58% less d6-α-CMBHC (0.017 ± 0.004 compared with 0.041 ± 0.004 mmol/g creatinine, respectively; P = 0.0009) and had 52% lower plasma d6-α-CEHC areas under the concentration curves [area under the curve from 0 to 24 h (AUC0-24h): 27.7 ± 7.9 compared with 58.4 ± 7.9 nmol/L × h, respectively; P = 0.01]. d6-α-CEHC peaked before d6-α-T in 77 of 80 paired plasma concentration curves. Urinary d6-α-CEHC 24-h concentrations were associated with the plasma AUC0-24 h of d6-α-T (r = 0.53, P = 0.02) and d6-α-CEHC (r = 0.72, P = 0.0003), and with urinary d6-α-CMBHC (r = 0.88, P < 0.0001), and inversely with the plasma inflammation biomarkers C-reactive protein (r = 20.70, P = 0.0006), interleukin-10 (r = 20.59, P = 0.007), and interleukin-6 (r = 20.54, P = 0.01). Conclusion: Urinary a-CEHC and a-CMBHC are useful biomarkers to noninvasively assess a-tocopherol adequacy, especially in populations with MetS-associated hepatic dysfunction that likely impairs a-tocopherol trafficking. This trial was registered at clinicaltrials.gov as NCT01787591. [ABSTRACT FROM AUTHOR]

Background: Little is known about α-tocopherol's bioavailability as a constituent of food or its dependence on a subject's age. Objective: To evaluate the α-tocopherol bioavailability from food, we used collard greens grown in deuterated water (2H collard greens) as a source of deuterium-labeled (2H) α-tocopherol consumed by younger and older adults in a post hoc analysis of a vitamin K study. Design: Younger (mean ± SD age: 32 ± 7 y; n = 12 women and 9 men) and older (aged 67 ± 8 y; n = 8 women and 12 men) adults consumed a test breakfast that included 120 g 2H collard greens (1.2 ± 0.1 mg 2H-α-tocopherol). Plasma unlabeled α-tocopherol and 2H-α-tocopherol were measured by using liquid chromatography-mass spectrometry from fasting ( > 12 h) blood samples drawn before breakfast (0 h) and at 24, 48, and 72 h and from postprandial samples collected at 4, 5, 6 , 7, 9, 12, and 16 h. Results: Times (12.6 ± 2.5 h) of maximum plasma 2H-α-tocopherol concentrations (0.82% ± 0.59% total α-tocopherol), fractional disappearance rates (0.63 ± 0.26 pools/d), half-lives (30 ± 11 h), and the minimum estimated 2H-α-tocopherol absorbed (24% ± 16%) did not vary between age groups or sexes (n = 41). Unlabeled α-tocopherol concentrations were higher in older adults (26.4 ± 8 .6 µmol/L) than in younger adults (19.3 ± 4.2 µmol/L; P = 0.0019) and correlated with serum lipids (r = 0.4938, P = 0.0012). In addition, 2H-a-tocopherol half-lives were correlated with lipids (r = 0.4361, P = 0.0044). Conclusions: Paradoxically, α-tocopherol remained in circulation longer in participants with higher serum lipids, but the 2H-α-tocopherol absorbed was not dependent on the plasma lipid status. Neither variable was dependent on age. These data suggest that plasma α-tocopherol concentrations are more dependent on mechanisms that control circulating lipids rather than those related to its absorption and initial incorporation into plasma. This trial was registered at clinicaltrials.gov as NCT0036232. Am J Clin Nutr 2015;101:752-9. [ABSTRACT FROM AUTHOR]

Chronic ethanol self-administration induces oxidative stress and exacerbates lipid peroxidation. α-Tocopherol is a potent lipid antioxidant and vitamin that is dependent upon lipoprotein transport for tissue delivery. To evaluate the extent to which vitamin E status is deranged by excessive alcohol consumption, monkeys voluntarily drinking ethanol (1.36 to 3.98 g/kg/d for 19 months, n = 11) were compared with nondrinkers ( n = 5, control). Three alcohol-drinking animals developed hyperlipidemia with plasma triglyceride levels (1.8 ± 0.9 mM) double those of normolipidemic (NL) drinkers (0.6 ± 0.2) and controls (0.6 ± 0.3, p < 0.05); elevated plasma cholesterol (3.6 ± 0.5 mM) compared with NL drinkers (2.3 ± 0.2, p < 0.05) and controls (2.9 ± 0.3); and lower plasma α-tocopherol per triglycerides (14 ± 6 mmol/mol) than controls (27 ± 8) and NL drinkers (23 ± 6, p < 0.05). Hyperlipidemic monkey liver α-tocopherol (47 ± 15 nmol/g) was lower than NL drinkers (65 ± 13) and controls (70 ± 15, p = 0.080), as was adipose α-tocopherol (84 ± 37 nmol/g) compared with controls (224 ± 118) and NL drinkers (285 ± 234, p < 0.05). Plasma apolipoprotein (apo) CIII increased compared to baseline at both 12 and 19 months in the normolipidemic ( p = 0.0016 and p = 0.0028, respectively) and in the hyperlipidemic drinkers ( p < 0.05 and p < 0.05, respectively). Plasma apo H concentrations at 19 months were elevated hyperlipidemics ( p < 0.05) relative to concentrations in control animals. C-reactive protein (CRP), a marker of inflammation, was increased compared to baseline at both the 12- and 19-month time points in the normolipidemic ( p = 0.005 and p = 0.0153, respectively) and hyperlipidemic drinkers ( p = 0.016 and p = 0.0201, respectively). A subset of alcohol-drinking monkeys showed a predisposition to alcohol-induced hyperlipidemia. The defect in lipid metabolism resulted in lower plasma α-tocopherol per triglycerides and depleted adipose tissue α-tocopherol, and thus decreased vitamin E status. [ABSTRACT FROM AUTHOR]

Abstract: Approximately 40% of Americans take dietary supplements, including vitamin E (α-tocopherol). Unlike other fat-soluble vitamins, α-tocopherol is not accumulated to toxic levels. Rather tissue levels are tightly regulated, in part via increased hepatic metabolism and excretion that could, theoretically, alter metabolism of drugs, environmental toxins, and other nutrients. To date, in vivo subcellular location(s) of α-tocopherol metabolism have not been identified. The proposed pathway of α-tocopherol metabolism proceeds via ω-hydroxylation to 13′-OH-α-tocopherol, followed by successive rounds of β-oxidation to form α-CEHC. To test the hypothesis that α-tocopherol ω-hydroxylation occurs in microsomes while β-oxidation occurs in peroxisomes, rats received daily injections of vehicle, 10 mg α-tocopherol, or 10 mg trolox/100 g body wt for 3 days, and then microsomes, mitochondria, and peroxisomes were isolated from liver homogenates. Homogenate α-tocopherol levels increased 16-fold in α-tocopherol-injected rats, while remaining unchanged in trolox- or vehicle-injected rats. Total α-tocopherol recovered in the three subcellular fractions represented 93±4% of homogenate α-tocopherol levels. In α-tocopherol-injected rats, microsome α-tocopherol levels increased 28-fold, while mitochondria and peroxisome levels increased 8- and 3-fold, respectively, indicating greater partitioning of α-tocopherol to the microsomes with increasing liver α-tocopherol. In α-tocopherol-injected rats, microsome 13′-OH-α-tocopherol levels increased 24-fold compared to controls, and were 7-fold greater than 13′-OH-α-tocopherol levels in peroxisome and mitochondrial fractions of α-tocopherol-injected rats. An unexpected finding was that α-CEHC, the end product of α-tocopherol metabolism, was found almost exclusively in mitochondria. These data are the first to indicate a mitochondrial role in α-tocopherol metabolism. [Copyright &y& Elsevier]

Alpha-tocopherol transfer protein (ATTP) null mice (ATTP−/−) have a systemic alpha-tocopherol (AT) deficiency, with their lung AT levels being < 10% of those in AT-replete ATTP+/+ mice when fed a standard rodent chow diet. ATTP+/+ and ATTP−/− mice (4 wk old male mice, n = 16 per group) were fed a standard diet (35 IU AT/kg diet) for 8–12 wk, exposed 6 h/day for 3 days to either to O3 (0.5 ppm) or filtered air, then sacrificed. No significant differences in plasma or lung AT concentrations were observed in response to this level of O3 exposure. Lung genomic responses of the lungs to O3 were determined using Affymetrix 430A 2.0 arrays containing over 22,600 probe sets representing 14,000 well-characterized mouse genes. As compared with filtered air exposure, O3 exposure resulted in 99 genes being differentially expressed in ATTP−/− mice, as compared to 52 differentially expressed genes in ATTP+/+ mice. The data revealed an O3-induced upregulation of genes related to cell proliferation/DNA repair and inflammatory-immune responses in both ATTP+/+ and ATTP−/− mice, with the expression of 22 genes being common to both, whereas 30 and 77 genes were unique to ATTP+/+ and ATTP−/− mice, respectively. The expressions of O3 sensitive genes— Timp1, Areg, Birc5 and Tnc—were seen to be further modulated by AT status. The present study reveals AT modulation of adaptive response of lung genome to O3 exposure. [ABSTRACT FROM AUTHOR]

Abstract: Muscle atrophy and weakness are predominant impairments after anterior cruciate ligament (ACL) surgical repair. We tested the hypothesis that vitamin E and C supplementation will improve recovery from ACL injury. Men undergoing elective ACL surgery were randomly assigned to twice-daily supplements of either antioxidants (AO; vitamins E and C, n =10) or matching placebos (n =10) from 2 weeks before until 3 months after surgery. Each subject provided several fasting blood draws, two muscle biopsies from the thigh muscle of the injured limb, and strength and thigh circumference measurements of the lower limbs. Muscle atrophy was apparent in both groups before and several days after surgery. Compared with baseline measurements, peak isometric force of the injured limb increased significantly (P <0.05) by 3 months postsurgery in both treatment groups; however, AO supplementation did not augment these strength gains. By contrast, baseline plasma ascorbic acid concentrations correlated (r =0.59, P =0.006) with subsequent improvement in the strength of the injured limb. In summary, vitamin E and C supplementation was ineffective in potentiating the improvement in force production by the injured limb; however, baseline vitamin C status was associated with beneficial outcomes in strength, suggesting that long-term dietary habits are more effective than short-term supplements. [Copyright &y& Elsevier]

Interleukin (IL)-10 is an anti-inflammatory cytokine that suppresses pro-inflammatory cytokines. We previously demonstrated that supplementation with vitamins E and C ameliorated the increase in IL-10 immediately following anterior cruciate ligament (ACL) surgery in the absence of other cytokine perturbations. Since both oxidative stress and insulin-like growth factor-1 (IGF-1) can modulate IL-10 concentrations, the mechanisms for these changes warranted further investigation. Our objective was to evaluate the mechanism for the IL-10 decrease following ACL surgery. This study consisted of randomized, double-blind, placebo-controlled experimental design. Subjects were randomly assigned to daily supplementation with either: (i) antioxidants (AO; vitamins E [α-tocopherol] and C [ascorbic acid]; n = 10); or (ii) matching placebos (PL; n = 10). Supplementation started ∼2 weeks prior to surgery (baseline) and concluded 3 months after surgery. Subjects provided six fasting blood samples at: (i) baseline; (ii) immediately pre-surgery (Pre); (iii) 90 min; (iv) 72 h; (v) 7 days; and (vi) 3 months post-surgery. α-Tocopherol, ascorbic acid, F2-isoprostane and IGF-1 concentrations were measured in each blood sample. At 90 min relative to other times, plasma F2-isoprostane concentrations were significantly (P < 0.05) elevated in both groups, while at 90 min IGF-1 was significantly (P < 0.05) lower in the AO compared to the PL group. The changes in IGF-1 at 90 min relative to baseline were correlated (P < 0.0001) with the changes in IL-10. The decrease in IL-10 observed in the AO group is likely dependent on the decrease IGF-1 since lipid peroxidation was unchanged between the two groups. [ABSTRACT FROM AUTHOR]

Abstract: Muscle atrophy commonly follows anterior cruciate ligament (ACL) injury and surgery. Proinflammatory cytokines can induce and exacerbate oxidative stress, potentiating muscle atrophy. The purpose of this study was to evaluate the influence of prior antioxidant (AO) supplementation on circulating cytokines following ACL surgery. A randomized, double-blind, placebo-controlled trial was conducted in men undergoing ACL surgery, who were randomly assigned to either: (1) AO (200 IU of vitamin E (50% d-alpha-tocopheryl acetate and 50% d-α-tocopherol) and 500 mg ascorbic acid), or (2) matching placebos (PL). Subjects took supplements twice daily for 2 weeks prior to and up to 12 weeks after surgery. Each subject provided five blood samples: (1) baseline (Bsl, prior to supplementation and ∼2 weeks prior to surgery), (2) presurgery (Pre), (3) 90 min, (4) 72 h, and (5) 7 days postsurgery. Following surgery, inflammation and muscle damage increased in both groups, as assessed by increased circulating IL-6, C-reactive protein, and creatine kinase. During AO supplementation, plasma α-T and AA increased while γ-T concentrations decreased significantly (P < 0.05). At 90 min the AO group displayed a significant decrease in AA, an inverse correlation between AA and (interleukin) IL-8 (r 2 = 0.50, P < 0.05), and a significantly lower IL-10 response than that of the PL group. IL-10 was significantly elevated at 90 min and 72 h in the PL group. In summary, our findings show that circulating inflammatory cytokines increase and AO supplementation attenuated the increase in IL-10 in patients post-ACL surgery. [Copyright &y& Elsevier]

Allergic asthma is a complex immunologically mediated disease associated with increased oxidative stress and altered antioxidant defenses. It was hypothesized that α-tocopherol (α-T) decreases oxidative stress and therefore its absence may influence allergic inflammatory process, a pathobiology known to be accompanied by oxidative stress. Therefore, selected parameters of allergic asthma sensitization and inflammation were evaluated following ovalbumin sensitization and re-challenge of α-T transfer protein (TTP) knock-out mice (TTP-/-) that have greatly reduced lung α-T levels (e.g.<5%) compared to their litter mate controls (TTP+/+). Results showed that severe α-T deficiency result in a blunted lung expression of IL-5 mRNA and IL-5 protein and plasma IgE levels compared with TTP+/+ mice following immune sensitization and rechallenge, although lung lavage eosinophil levels were comparable in both genomic strains. It is concluded that the initial stimulation of immune responses by the TTP-/- mice were generally blunted compared to the TTP+/+ mice, thus diminishing some aspects of subsequent allergic inflammatory processes. [ABSTRACT FROM AUTHOR]

Purpose. The effects of vitamin E supplementation on the cholesterol levels of hypercholesterolemic patients receiving statin therapy were studied. Methods. In this prospective, single-blind, placebo-controlled, randomized trial, patients who were currently taking either lovastatin or simvastatin for a primary diagnosis of hypercholesterolemia were given placebo for two weeks and then randomized to receive a supplement of either 400 IU of vitamin E or matching placebo after dinner for eight weeks, followed by a two-week washout period. Results. Vitamin E supplementation increased plasma α-tocopherol concentrations approximately 1.6-fold and increased excretion of its urinary metabolite 4-fold significantly from week 2 to week 6 (p < 0.001 for both comparisons). During the eight-week supplementation period, no statistically significant differences in any lipoprotein cholesterol fraction were detected between groups; however, a 6% decrease in high-density-lipoprotein (HDL) cholesterol was detected within the vitamin E group from week 2 to week 6 (p < 0.05), but the decrease was not sufficient to change the cardiac risk ratio. Neither cytochrome P-450 isoenzyme (CYP) 3A (as measured by hydroxylation of urinary cortisol) nor cholesteryl ester transfer protein (CETP) activity was significantly altered during the study. Conclusion. Vitamin E supplementation did not affect total or low-density-lipoprotein cholesterol levels in hypercholesterolemic patients receiving lovastatin or simvastatin. A small but significant decrease in HDL cholesterol levels was observed in the group that received vitamin E supplementation during the supplementation period, but this decrease was no longer significantly different from the placebo group's levels two weeks post-supplementation. The decrease in HDL cholesterol levels did not appear to be related to either CYP3A or CETP. [ABSTRACT FROM AUTHOR]

α-tocopherol (α-T) may affect biological processes by modulating mRNA concentrations. This study screened the responses of &nvsim;15,000 lung mRNAs to dietary α-T in mice. The lung was chosen as the target organ because it is subjected to cyclical variations in oxidant and inflammatory stressors and α-T has been implicated in their modulations. The analysis identified &nvsim;400 mRNAs sensitive to α-T status of lungs determined by dietary α-T. The female lung transcriptome appears to be more sensitive to the α-T status than that of the male lungs. Here, we focus on the induction of 13 cytoskeleton genes by dietary α-T because they were similarly induced in the male and the female lungs. Their inductions were confirmed by quantitative-real-time-polymerase chain reaction (qRT-PCR). Immunohistochemical analyses of three of the encoded proteins suggest that they are expressed in lung vasculature and alveolar regions. The data suggest that the lung α-T status may modulate cytoarchitecture of lungs. [ABSTRACT FROM AUTHOR]

Abstract: To test the hypothesis that supra-elevated hepatic α-tocopherol concentrations would up-regulate mechanisms that result in increased hepatic α-tocopherol metabolism and excretion, rats received daily subcutaneous α-tocopherol injections (10 mg/100 g body wt) and then were sacrificed on Day 0 or 12 h following their previous injection on Days 3, 6, 9, 12, 15, and 18. Liver α-tocopherol concentrations increased from 12±1 nmol/g (mean±SE) to 819±74 (Day 3), decreased at Day 9 (486±67), and continued to decrease through Day 18 (338±37). α-Tocopherol metabolites and their intermediates increased and decreased similarly to α-tocopherol albeit at lower concentrations. There were no changes in known vitamin E regulatory proteins, i.e., hepatic α-tocopherol transfer protein or cytochrome P450 (CYP) 4F. In contrast, both CYP3A and CYP2B, key xenobiotic metabolizing enzymes, doubled by Day 6 and remained elevated, while P450 reductase increased more slowly. Consistent with the decrease in liver α-tocopherol concentrations, a protein involved in biliary xenobiotic excretion, p-glycoprotein, increased at Day 9, doubling by Day 15. Thus hepatic α-tocopherol concentrations altered hepatic proteins involved in metabolism and disposition of xenobiotic agents. [Copyright &y& Elsevier]

Wildtype sunflower ( Helianthus annuus L.) seeds are a rich source of α-tocopherol (vitamin E). The g = Tph 2 mutation disrupts the synthesis of α-tocopherol, enhances the synthesis of γ-tocopherol, and was predicted to knock out a γ-tocopherol methyltransferase (γ-TMT) necessary for the synthesis of α-tocopherol in sunflower seeds—wildtype ( g + g +) lines accumulated > 90% α-tocopherol, whereas mutant ( g g) lines accumulated > 90% γ-tocopherol. We identified and isolated two γ- TMT paralogs (γ- TMT-1 and γ- TMT-2). Both mapped to linkage group 8, cosegregated with the g locus, and were transcribed in developing seeds of wildtype lines. The g mutation greatly decreased γ -TMT-1 transcription, caused alternative splicing of γ -TMT-1, disrupted γ- TMT-2 transcription, and knocked out one of two transcription initiation sites identified in the wildtype; γ- TMT transcription was 36 to 51-fold greater in developing seeds of wildtype ( g + g +) than mutant ( g g) lines. F2 populations (B109 × LG24 and R112 × LG24) developed for mapping the g locus segregated for a previously unidentified locus ( d). B109, R112, and LG24 were homozygous for a null mutation ( m = Tph 1) in MT-1, one of two 2-methyl-6-phytyl-1,4-benzoquinone/2-methyl-6-solanyl-1,4-benzoquinone methyltransferase ( MPBQ/MSBQ-MT) paralogs identified in sunflower. The d mutations segregating in B109 × LG24 and R112 × LG24 were allelic to a cryptic mutation identified in the other MPBQ/MSBQ-MT paralog ( MT-2) and disrupted the synthesis of α- and γ-tocopherol in F2 progeny carrying m or g mutations— m m g + g + d d homozygotes accumulated 41.5% α- and 58.5% β-T, whereas m m g g d d homozygotes accumulated 58.1% γ- and 41.9% δ-T. MT-2 cosegregated with d and mapped to linkage group 4. Hence, novel tocopherol profiles are produced in sunflower seed oil by three non-allelic epistatically interacting methyltransferase mutations. [ABSTRACT FROM AUTHOR]

Introduction: A decrease in α-tocopherol (vitamin E) plasma levels in burn patients is typically associated with increased mortality. We hypothesized that vitamin E supplementation (α-tocopherol) would attenuate acute lung injury induced by burn and smoke inhalation injury. Materials and Methods: Under deep anesthesia, sheep (33 ± 5 kg) were subjected to a flame burn (40% total body surface area, third degree) and inhalation injury (48 breaths of cotton smoke, < 40°C). Half of the injured group received α-tocopherol (1000 IU vitamin E) orally, 24 h prior to injury. The sham group was neither injured nor given vitamin E. All three groups (n = 5 per group) were resuscitated with Ringer's lactate solution (4 ml/kg/%burn/24 h), and placed on a ventilator (PEEP = 5 cmH2O; tidal volume = 15 ml/kg) for 48 h. Results: Plasma α-tocopherol per lipids doubled in the vitamin E treated sheep. Vitamin E treatment prior to injury largely prevented the increase in pulmonary permeability index and moderated the increase in lung lymph flow (52.6 ± 6.2 ml/min, compared with 27.3 ± 6.0 ml/min, respectively), increased the PaO2/FiO2 ratio, ameliorated both peak and pause airway pressure increases, and decreased plasma conjugated dienes and nitrotyrosine. Conclusions: Pretreatment with vitamin E ameliorated the acute lung injury caused by burn and smoke inhalation exposure. [ABSTRACT FROM AUTHOR]

Abstract: Vitamin E disappearance is accelerated in cigarette smokers due to their increased oxidative stress and is inversely correlated with plasma vitamin C concentrations. Therefore, we hypothesized that ascorbic acid supplementation (500 mg, twice daily; 2 weeks) would normalize smokers'' plasma α- and γ-tocopherol disappearance rates and conducted a double-blind, placebo-controlled, randomized crossover investigation in smokers (n = 11) and nonsmokers (n = 13) given a single dose of deuterium-labeled α- and γ-tocopherols (50 mg each d6-RRR-α and d2-RRR-γ-tocopheryl acetate). During the placebo trial, smokers, compared with nonsmokers, had significantly (P < 0.05) greater α- and γ-tocopherol fractional disappearance rates and shorter half-lives. Ascorbic acid supplementation doubled (P < 0.0001) plasma ascorbic acid concentrations in both groups and attenuated smokers'', but not nonsmokers'', plasma α- and γ-tocopherol (P < 0.05) fractional disappearance rates by 25% and 45%, respectively. Likewise, smokers'' plasma deuterium-labeled α- and γ-tocopherol concentrations were significantly higher (P < 0.05) at 72 h during ascorbic acid supplementation compared with placebo. Ascorbic acid supplementation did not significantly change (P > 0.05) time of maximal or maximal-labeled α- and γ-tocopherol concentrations. Smokers'' plasma F2α-isoprostanes were ∼26% higher than nonsmokers (P > 0.05) and were not affected by ascorbic acid supplementation in either group (P > 0.05). In summary, cigarette smoking increased plasma α- and γ-tocopherol fractional disappearance rates, suggesting that the oxidative stress from smoking oxidizes tocopherols and that plasma ascorbic acid reduces α- and γ-tocopheroxyl radicals to nonoxidized forms, thereby decreasing vitamin E disappearance in humans. [Copyright &y& Elsevier]

Cigarette smoking (CS) is a well-described oxidant burden in humans. We hypothesized that CS would accelerate α-tocopherol (α-T) utilization leaving less for metabolite (CEHC) production. After labeled α-T consumption (75 mg each of d3-RRR-α-TAc and d6-all-rac-α-TAc) by smokers and nonsmokers (n = 10/group), CS increased α-T disappearance and decreased plasma and urinary CEHCs. Plasma d3/d6-α-T ratios were approximately 1.4 during supplementation and approximately 2 from days 5 to 17. d3/d6-α-CEHC ratios were on average 0.29 ± 0.05, confirming that all-rac-α-tocopherol is metabolized more efficiently. CEHC may be a good marker of vitamin E status, and smokers may have an increased vitamin E requirement. [ABSTRACT FROM AUTHOR]

Enrichment of skin surface lipids with deuterium-labeled α-tocopherol was compared with plasma enrichment to evaluate kinetics of the delivery of vitamin E to skin surface lipids. For 7 d, subjects consumed 75 mg each of RRR-α-[5-(C2H3)]- (d3) and all rac-α-[5,7-(C2H3)2]- (d6) tocopheryl acetates with breakfast. Blood was drawn and skin lipids were collected daily for 2 weeks, then every other day for 2 weeks. A liquid chromatography–mass spectrometry atmospheric pressure chemical ionization method for quantification of deuterium labeled (d3, d6, d9-α-tocopherols) and unlabeled (d0-) α- and γ-tocopherols was developed. Tocopherols were quantified at their m/z [M-1] using single ion recording. α-Tocopherol detection was linear from 1 to 100 pmol with a detection limit of 40 pg (93 fmol). Detection of γ-tocopherol was twice as sensitive due to greater ionization efficiency. Though d3- and d6-α-tocopherols appeared in plasma within 24 h of the first dose, d3-α-tocopherol was not detected in skin surface lipids until ∼1 week. Plasma percentage d3 peaked at day 8, while skin surface lipid percentage d3 increased on average until day 19. Apparently skin employs a mechanism to deliver α-tocopherol into skin via lipid secretions. [Copyright &y& Elsevier]

We hypothesized that the high concentrations of reactive nitrogen species in cigarette smoke and the known stimulatory effects of cigarette smoke on the inflammatory immune systems would lead to the formation of 5-nitro-γ-tocopherol (NGT). In order to assess γ-tocopherol nitration, human plasma was exposed in vitro to gas phase cigarette smoke (GPCS) or air for up to 6 h. A liquid chromatography-mass spectrometry (LC-MS) method was developed to quantitate NGT. Detector response was linear from 0.1 to 3 pmol NGT, with a detection limit of 20 fmol. After a 1 h lag time, 6 h plasma exposure to GPCS depleted ∼ 75% of α-T, ∼ 60% of γ-T and increased NGT from 3 to 134 nmol/l. The increase in NGT accounted for ∼ 20% of the γ-T decrease. NGT also correlated (R2 = 0.9043) with nitrate concentrations in GPCS-exposed plasma. The physiologic relevance of NGT was evaluated in a group of healthy humans. Smokers (n = 15) had plasma NGT concentrations double those of nonsmokers (n = 19), regardless of corrections using lipids or γ-T; plasma α-T and γ-T concentrations were similar between the groups. Our results show that LC-MS can be successfully used for NGT quantitation in biologic samples. Importantly, NGT in smokers'' plasma suggests that cigarette smoking causes increased nitrosative stress. [Copyright &y& Elsevier]

Background: Most vitamin E supplements contain synthetic all-rac-α-tocopherol [2,5,7,8-tetramethyl-2RS-(4'RS,8'RS,12- trimethyltridecyl)-6-chromanol] with 8 stereoisomers; only 1 is identical to the natural stereoisomer, RRR-α-tocopherol [2,5,7,8- tetramethyl-2R-(4'R,8'R,12-trimethyltridecyl)-6-chromanol]. In humans, 2R-α-tocopherol stereoisomers are preferentially maintained in the plasma, a function that has been attributed to hepatic α-tocopherol transfer protein (α-TTP), but this hypothesis has not been tested. Objective: We sought to determine the functions of α-TTP by comparing mice that express α-TTP with mice that are genetically unable to express α-TTP. Design: Adult α-TTP null (Ttpa-/-; n = 5), heterozygous (Ttpa+/-; n = 7), and wild-type (Ttpa+/+; n = 3) mice consumed equimolar RRR-α-[5,7-(C2H3)2]-(d6)- and all-rac-α-[5-(C2H3)]-(d3)-tocopheryl acetates (30 mg/kg diet each) for 3 mo. Subsequently, we measured labeled and unlabeled α-tocopherols in plasma and 17 tissues. Results: In all mice, plasma and tissue d6- + d3-α-tocopherols represented ≈80-90% of total α-tocopherol. In the Ttpa-/- mice, low total α-tocopherol concentrations were found in plasma (5.4%) and most other tissues (2-20%), but liver concentrations were 39% of those of Ttpa+/+ mice. Peripheral tissue ratios of d6- tod3-α-tocopherol were 1.1 ± 0.1 and 1.8 ± 0.2 in Ttpa-/- and Ttpa+/+ mice, respectively (P < 0.0001), showing that α-TTP preferentially selects 2R-α-tocopherols for secretion into plasma. This 2:1 ratio does not support the currently defined international unit of 1.36:1 RRR-α-tocopherol to all-rac-α-tocopherol. Conclusion: Deletion of the α-TTP gene in mice results in an accumulation of dietary α-tocopherol in the liver and depletion of peripheral tissue α-tocopherol. [ABSTRACT FROM AUTHOR]

In rats, sesame lignans increase plasma γ-tocopherol (γ-TOH) concentrations and inhibit γ-TOH degradation to its metabolite γ-carboxyethylhydroxychroman γ-CEHC). To test if sesame lignan consumption inhibits γ-TOH metabolism in humans, muffins prepared with either corn oil (control) or sesame oil and an equimolar mixture of deuterium labeled d6-α- and d2-γ-TOH were administered to male (n=5) and female (n=5) volunteers. TOH and CEHC concentrations were followed for 72 h. Sesame lignan consumption significantly increased plasma d2-γ-TOH concentrations (p<0.05). In men, sesame lignans increased the area under the curve (AUC; sesame oil: 34.3 4- 4.6; corn oil: 28.9 ± 3.3 µmol/L·h, p<0.01) of d2-γ-TOH and reduced d2-γ-CEHC AUCs in plasma (p<0.05). The differences in urinary d2-γ-CEHC AUCs in men did not reach statistical significance (AUCs for 24 h, corn oil: 11.2 ± 3.0 gmol/g creatinine·h; vs sesame oil: 5.0 ± 1.5). In women, sesame lignan consumption did not alter plasma TOH and CEHC concentrations but reduced urinary d2-γ-CEHC excretion (AUCs for 24 h, corn oil: 19.3 ± 4.9 µmol/g creatinine·h; and sesame oil: 7.7 ± 2.0, p < 0.05). These data suggest that sesame lignans alter γ-TOH metabolism differently in men and women. [ABSTRACT FROM AUTHOR]

Abstract: The role of hepatic xenobiotic regulatory mechanisms in modulating hepatic α-tocopherol concentrations during excess vitamin E administration remains unclear. We hypothesized that increased hepatic α-tocopherol would cause a marked xenobiotic response. Thus, we assessed cytochrome P450 oxidation systems (phase I), conjugation systems (phase II), and transporters (phase III) after daily α-tocopherol injections (100mg/kg body wt) for up to 9days in rats. α-Tocopherol injections increased hepatic α-tocopherol concentrations nearly 20-fold, along with a 10-fold increase in the hepatic α-tocopherol metabolites α-CEHC and α-CMBHC. Expression of phase I (CYP3A2, CYP3A1, CYP2B2) and phase II (SULT2A1) proteins and/or mRNAs was variably affected by α-tocopherol injections; however, expression of phase III transporter genes was consistently changed by α-tocopherol. Two liver efflux transporter genes, ABCB1b and ABCG2, were up-regulated after α-tocopherol injections, whereas OATP, a liver influx transporter, was down-regulated. Thus, an overload of hepatic α-tocopherol increases its own metabolism and increases expression of genes of transporters that are postulated to lead to increased excretion of both vitamin E and its metabolites. [Copyright &y& Elsevier]

Abstract: Approximately 12% of Americans do not consume the estimated average requirement for zinc and could be at risk for zinc deficiency. Since zinc has proposed antioxidant function, inadequate zinc consumption may lead to an enhanced susceptibility to oxidative stress through several mechanisms, including altered antioxidant defenses. In this study, we hypothesized that dietary zinc restriction would result in lower antioxidant status and increased oxidative damage. We fed weanling Sprague–Dawley rats (n=12 per group) a zinc-adequate (50 mg/kg of zinc) diet, a zinc-deficient (<0.05 mg/kg of zinc) diet or a pair-fed diet for 3 weeks and then assessed their antioxidant status and oxidative stress parameters. Rats were zinc deficient as indicated by a significant (P<.05) reduction in body weight (49%) and 19% lower (P<.05) hepatic zinc (20.6±2.1 mg/kg) as compared with zinc-adequate rats (24.6±2.2 mg/kg). Zinc deficiency resulted in elevated (P<.05) plasma F2 isoprostanes. Zinc deficiency-mediated oxidative stress was accompanied by a 20% decrease (P<.05) in the ferritin-reducing ability of plasma assay and a 50% reduction in plasma uric acid (P<.05). No significant change in plasma ascorbic acid or in plasma α-tocopherol and γ-tocopherol was observed. However, hepatic α-tocopherol and γ-tocopherol concentrations were decreased by 38% and 27% (P<.05), respectively, as compared with those in zinc-adequate rats. Hepatic α-tocopherol transfer protein levels were unaltered (P>.05) by zinc deficiency, but cytochrome P450 (CYP) 4F2 protein levels were elevated (P<.05) as compared with those in zinc-adequate rats. Collectively, zinc deficiency increased oxidative stress, which may be partially explained by increased CYP activity and reductions in hepatic α-tocopherol and γ-tocopherol and in plasma uric acid. [Copyright &y& Elsevier]

An evaluation of the impact of vitamin E deficiency on expression of the alpha-tocopherol transfer protein (α-TTP) and related CRAL_TRIO genes was undertaken using livers from adult zebrafish based on the hypothesis that increased lipid peroxidation would modulate gene expression. Zebrafish were fed either a vitamin E sufficient (E+) or deficient (E-) diet for 9 months, then fish were euthanized, and livers were harvested. Livers from the E+ relative to E- fish contained 40-times more α-tocopherol (P <0.0001) and one fourth the malondialdehyde (P = 0.0153). RNA was extracted from E+ and E- livers, then subject to evaluation of gene expression of ttpa and other genes of the CRAL_TRIO family, genes of antioxidant markers, and genes related to lipid metabolism. Ttpa expression was not altered by vitamin E status. However, one member of the CRAL_TRIO family, tyrosine-protein phosphatase non-receptor type 9 gene (ptpn9a), showed a 2.4-fold increase (P = 0.029) in E- relative to E+ livers. Further, we identified that the gene for choline kinase alpha (chka) showed a 3.0-fold increase (P = 0.010) in E- livers. These outcomes are consistent with our previous findings that show vitamin E deficiency increased lipid peroxidation causing increases in phospholipid turnover. [ABSTRACT FROM AUTHOR]

Hazelnut kernels obtained from the commercial processes were analyzed for proximate composition, bioactive compounds, lipid oxidation, and enzyme (lipase, peroxidase, and polyphenol oxidase) activities and compared among three cultivars (Barcelona, Yamhill, and Jefferson) and two agricultural practices (with and without fertigation for Jefferson). The influence of drying temperature (38, 43, and 49 °C) and relative humidity (RH, 40 and 60%) on drying characteristics (drying rates of inshells and corresponding moisture content (MC) and water activity (a w ) of kernels when inshells reached ∼10 g/100 g MC or equilibrium MC (MC eq )), bioactive compounds, lipid oxidation, and enzyme activity of the kernels were investigated. Oleic acid and α-tocopherol were the predominant fatty acids and vitamin in hazelnuts. Yamhill contained the highest phenolic (0.12 mg GAE/g), vitamin E (14.26 mg/100 g, α-tocopherol), and lowest unsaturated/saturated fatty acids ratio (8.7) among cultivars. Drying characteristics and chemical and enzymatic reactions of hazelnuts varied depending on drying condition and cultivar of nuts, in which drying at 43–49 °C and 40% RH improved drying efficiency and retained quality of dried hazelnuts. This study suggested the ideal drying conditions that could produce dried hazelnuts with optimal range of MC and a w for retaining bioactive compounds and minimizing lipid oxidation and enzyme activity. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the impact of the dietary antioxidants, vitamin E and C, on inflammatory cytokines and the association between reciprocally regulated cytokines following an anterior ligament surgery. It measures the plasma inflammatory cytokines in blood samples before and after the surgery. The results show the ineffectiveness of vitamin E and C in improving the increase in plasma interleukin (IL) 1β and their ability to alter associations between cytokines.

Abstract: The aryl hydrocarbon receptor (AhR) is involved in regulation of mechanisms for detoxification of xenobiotics, as well as vitamin A metabolism. Vitamin E is a fat-soluble nutrient whose metabolism is initialized via the cytochrome P450 system. Thus, AhR absence could alter hepatic regulation of α-tocopherol metabolism. To test this hypothesis, we assessed vitamin E status in adult (2-5 m) and old (21-22 m), wild-type and AhR-null mice. Plasma α-tocopherol concentrations in AhR-null mice (2.3±1.2 μmol/L, n=19) were lower than those of wild-type mice (3.2±1.2, n=17, P=.0131); those in old mice (3.2±1.2, n=20) were higher than those of adults (2.2±1.0, n=16, P=.0075). Hepatic α-tocopherol concentrations were not different between genotypes, but were nearly double in old (32±8 nmol/g, n=20) as compared with adult mice (17±2, n=16, P<.0001). Hepatic Cyp3a concentrations in AhR-null mice were greater than those in wild-type mice (P=.0011). Genotype (P=.0047), sex (P<.0001) and age (P<.0001) were significant modifiers of liver α-tocopherol metabolite (α-CEHC) concentrations. In general, Cyp3a concentrations correlated with hepatic α-tocopherol (r=0.3957, P<.05) and α-CEHC (r=0.4260, P<.05) concentrations. Since there were no significant genotype differences in the hepatic α- or γ-tocopherol concentrations, AhR-null mice did not have dramatically altered vitamin E metabolism. Since they did have higher hepatic α-CEHC concentrations, these data suggest metabolism was up-regulated in the AhR-null mice in order to maintain the hepatic tocopherol concentrations similar to those of wild-type mice. [ABSTRACT FROM AUTHOR]

Abstract: Hepatic proteins involved in xenobiotic pathways (Phases I, II and III) are responsible for the metabolism and disposition of endogenous and exogenous compounds including dietary phytochemicals. To test the hypothesis that elevated α-tocopherol intakes alter gene expression of hepatic xenobiotic pathways, mice were fed diets supplemented with either 1000 IU (+E) or 35 IU (E) all-rac-α-tocopheryl acetate for 4 months; liver RNA was isolated, and gene expression was determined using both whole genome microarray and real-time quantitative polymerase chain reaction analyses. Hepatic α-tocopherol (173±18 vs. 21±1 nmol/g, mean±S.E.) and its metabolite (2,5,7,8-tetramethyl-2-(2′-carboxyethyl)-6-hydroxychroman, 0.232±0.046 vs. 0.031±0.019 nmol/g) concentrations were approximately eightfold higher following the +E dietary treatment. In +E relative to E mice, gene expression of Phase I enzymes, P450 oxidoreductase and cytochrome P450 3a11 increased 1.6- and 4.0-fold, respectively; two Phase II genes, sulfotransferase 2a and glutathione S-transferase mu 3, increased 10.8- and 1.9-fold respectively, and a Phase III biliary transporter, Abcb1a, doubled. Thus, consumption of high-level dietary α-tocopherol simultaneously coordinated Phase I, II and III gene expression. These data demonstrate that increased hepatic α-tocopherol modulates its own concentrations through increasing xenobiotic metabolism, a process that may alter metabolism of other foreign compounds, such as therapeutic drugs and phytochemicals, in humans. [Copyright &y& Elsevier]

Abstract: To test the hypothesis that hepatic regulation of α-tocopherol metabolism would be sufficient to prevent overaccumulation of α-tocopherol in extrahepatic tissues and that administration of high doses of α-tocopherol would up-regulate extrahepatic xenobiotic pathways, rats received daily subcutaneous injections of either vehicle or 0.5, 1, 2, or 10 mg α-tocopherol/100 g body wt for 9 days. Liver α-tocopherol increased 15-fold in rats given 10 mg α-tocopherol/100 g body wt (mg/100 g) compared with controls. Hepatic α-tocopherol metabolites increased with increasing α-tocopherol doses, reaching 40-fold in rats given the highest dose. In rats injected with 10 mg/100 g, lung and duodenum α-tocopherol concentrations increased 3-fold, whereas α-tocopherol concentrations of other extrahepatic tissues increased 2-fold or less. With the exception of muscle, daily administration of less than 2 mg/100 g failed to increase α-tocopherol concentrations in extrahepatic tissues. Lung cytochrome P450 3A and 1A levels were unchanged by administration of α-tocopherol at any dose. In contrast, lung P-glycoprotein (MDR1) levels increased dose dependently and expression of this xenobiotic transport protein was correlated with lung α-tocopherol concentrations (R 2 =0.88, p <0.05). Increased lung MDR1 may provide protection from exposure to environmental toxins by increasing alveolar space α-tocopherol. [Copyright &y& Elsevier]

The liver preferentially secretes α-tocopherol into plasma under the control of the hepatic α-tocopherol transfer protein (α-TTP). α-TTP-null mice (Ttpa−/− mice) are vitamin E deficient, therefore were used for investigations of in vivo responses to sub-normal tissue α-tocopherol concentrations during inflammation. Increased basal oxidative stress in Ttpa−/− mice was documented by increased plasma lipid peroxidation, and superoxide production by bone marrow-derived neutrophils stimulated in vitro with phorbol 12-myristate 13-acetate. Lipopolysaccharide (LPS) injected intraperitoneally induced increases in lung and liver HO-1 and iNOS, as well as plasma NOx in Ttpa+/+ mice. LPS induced more modest increases in these markers in Ttpa−/− mice, while more marked increases in plasma IL-10 and lung lavage TNFα were observed. Taken together, these results demonstrate that α-tocopherol is important for proper modulation of inflammatory responses and that sub-optimal α-tocopherol concentrations may derange inflammatory–immune responses. [Copyright &y& Elsevier]