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Biomedical subjects

John K Lodge

Publications and source records attributed to John K Lodge.

12 recordsLinked to original sources
PubMed2006

Cigarette smokers differ in their handling of natural (RRR) and synthetic (all rac) alpha-tocopherol: a biokinetic study in apoE4 male subjects.

We have compared the biokinetics of deuterated natural (RRR) and synthetic (all rac) alpha-tocopherol in male apoE4-carrying smokers and nonsmokers. In a randomized, crossover study subjects underwent two 4-week treatments (400 mg/day) with undeuterated RRR- and all rac-alpha-tocopheryl acetate around a 12-week washout. Before and after each supplementation period subjects underwent a biokinetic protocol (48 h) with 150 mg deuterated RRR- or all rac-alpha-tocopheryl acetate. During the biokinetic protocols, the elimination of endogenous plasma alpha-tocopherol was significantly faster in smokers (P < 0.05). However, smokers had a lower uptake of deuterated RRR than nonsmokers, but there was no difference in uptake of deuterated all rac. The supplementation regimes significantly raised plasma alpha-tocopherol (P < 0.001) with no differences in response between smokers and nonsmokers or between alpha-tocopherol forms. Smokers had significantly lower excretion of alpha-carboxyethyl-hydroxychroman than nonsmokers following supplementation (P < 0.05). Nonsmokers excreted more alpha-carboxyethyl-hydroxychroman following RRR than all rac; however, smokers did not differ in excretion between forms. At baseline, smokers had significantly lower ascorbate (P < 0.01) and higher F(2)-isoprostanes (P < 0.05). F(2)-isoprostanes in smokers remained unchanged during the study, but increased in nonsmokers following alpha-tocopherol supplementation. These data suggest that apoE4-carrying smokers and nonsmokers differ in their handling of natural and synthetic alpha-tocopherol.

Adult↗
PubMed2005

Dietary vitamin C down-regulates inflammatory gene expression in apoE4 smokers.

The deleterious impact of cigarette smoking on cardiovascular health may be in part attributable to a free radical mediated proinflammatory response in circulating monocytes. In the current investigation, the impact of vitamin C supplementation on monocyte gene expression was determined in apoE4 smokers versus non-smokers. A total of 10 smokers and 11 non-smokers consumed 60mg/day of vitamin C for four weeks and a fasting blood sample was taken at baseline and post-intervention for the determination of plasma vitamin C and monocyte gene expression profiles using cDNA array and real time PCR. In apoE4 smokers, supplementation resulted in a 43% increase in plasma vitamin C concentrations. Furthermore, a number of genes were differentially expressed more than 2-fold in response to treatment, including a downregulation of the proinflammatory mediators tumor necrosis factor (TNF) beta, TNF receptor, neurotrophin-3 growth factor receptor, and monocyte chemoattractant protein 1 receptor. The study has identified a number of molecular mechanisms underlying the benefit of vitamin C supplementation in smokers.

Adult↗
PubMed2005

Vitamin E bioavailability in humans.

It is important to understand factors that can influence vitamin E bioavailability, particularly in populations with increased risk of coronary heart disease such as cigarette smokers. There is also a need to clarify the bioavailability of natural and synthetic vitamin E, which is currently a subject of some controversy. Previous studies using a competitive uptake approach have found bioavailability ratios of natural:synthetic vitamin E close to 2:1, differing from the accepted biopotency ratio of 1.36:1. We used a non-competitive uptake approach to compare the plasma biokinetics of deuterated natural (RRR) and synthetic (all rac) alpha-tocopheryl acetate in smokers and non-smokers. The study was comprised of two 4-week treatments with 400 mg/d (either RRR-alpha-tocopheryl or all rac-alpha-tocopheryl acetates), with a 12-week washout period between. Prior to and after each treatment subjects underwent a 48 h biokinetic protocol with 150 mg deuterated alpha-tocopheryl acetate in either the RRR or all rac form. Smokers had a lower deuterated alpha-tocopherol AUC than did non-smokers following administration of RRR, but there was no difference following administration of all rac. The ratio RRR:all rac from AUCs and C(max) was 1.3:1 in non-smokers and 0.9:1 in smokers. Following vitamin E supplementation, deuterated tocopherol AUCs were lower in both groups. These data suggest that non-smokers and smokers differ in their handling of vitamin E, that the relative bioavailability of natural and synthetic vitamin E is close to the currently accepted biopotency ratio of 1.36:1, and that following supplementation the ability of the plasma to take up newly absorbed vitamin E is decreased.

Apolipoprotein E4↗
PubMed2005

Comparative (2)H-labelled alpha-tocopherol biokinetics in plasma, lipoproteins, erythrocytes, platelets and lymphocytes in normolipidaemic males.

The biokinetics of newly absorbed vitamin E in blood components was investigated in normolipidaemic males. Subjects (n 12) ingested encapsulated 150 mg (2)H-labelled RRR-alpha-tocopheryl acetate with a standard meal. Blood was collected at 3, 6, 9, 12, 24 and 48 h post-ingestion. (2)H-Labelled and pre-existing unlabelled alpha-tocopherol (alpha-T) was determined in plasma, lipoproteins, erythrocytes, platelets and lymphocytes by LC-MS. In all blood components, labelled alpha-T concentration significantly increased while unlabelled decreased following ingestion (P<0.0001). Significant differences in labelled alpha-T biokinetic parameters were found between lipoproteins. Time of maximum concentration was significantly lower in chylomicrons, while VLDL had a significantly greater maximum alpha-T concentration and area under the curve (AUC) (P<0.05). The largest variability occurred in chylomicron alpha-T transport. Erythrocyte labelled alpha-T concentrations increased gradually up to 24 h while alpha-T enrichment of platelets and lymphocytes was slower, plateauing at 48 h. Platelet enrichment with labelled alpha-T was biphasic, the initial peak coinciding with the labelled alpha-T peak in chylomicrons. Erythrocyte and HDL AUC were significantly correlated (P<0.005), as was platelet and HDL AUC (P<0.05). There was a lower turnover of pre-existing alpha-T in platelets and lymphocytes (maximum 25 % labelled alpha-T) compared to plasma and erythrocytes (maximum 45 % labelled alpha-T). These data indicate that different processes exist in the uptake and turnover of alpha-T by blood components and that chylomicron alpha-T transport is a major determinant of inter-individual variation in vitamin E response. This is important for the understanding of alpha-T transport and uptake into tissues.

Adult↗
PubMed2005

Hyperlipidemic subjects have reduced uptake of newly absorbed vitamin E into their plasma lipoproteins, erythrocytes, platelets, and lymphocytes, as studied by deuterium-labeled alpha-tocopherol biokinetics.

Vitamin E homeostasis in hyperlipidemia is poorly understood. The biokinetics of deuterated alpha-tocopherol (alpha-T) in blood components was investigated in normolipidemic (N; total cholesterol < 5.5 mmol/L and triglycerides < 1.5 mmol/L, n = 9), hypercholesterolemic (HC; total cholesterol > 6.5 mmol/L and triglycerides < 1.5 mmol/L, n = 10), and combined hypercholesterolemic and hypertriglyceridemic (HCT; total cholesterol > 6.5 mmol/L and triglycerides > 2.5 mmol/L, n = 6) subjects. Subjects ingested 150 mg hexadeuterated RRR-alpha-tocopheryl acetate, and blood was collected up to 48 h after ingestion. Labeled alpha-T was measured in plasma, lipoproteins, erythrocytes, platelets, and lymphocytes by liquid chromatography/mass spectroscopy. In plasma, HC had an earlier time of maximum concentration (6 h) compared with N and HCT (12 h) (P < 0.05). HCT had a lower uptake of labeled alpha-T (P < 0.005) and a longer half-life (P < 0.05). In chylomicrons, the maximum labeled alpha-T concentration was higher in HC compared with N and HCT (P < 0.00005); however, HCT had a lower uptake of labeled alpha-T in LDL. In all groups, the lowest density LDL subfraction contained more labeled alpha-T than denser subfractions (P < 0.05). In platelets, lymphocytes, and erythrocytes, the areas under the labeled alpha-T concentration vs. time curves were in the order N > HC > HCT. In lymphocytes, differences in labeled alpha-T were found at 6 and 48 h (P < 0.05). These data demonstrate that there are differences in the uptake of newly absorbed alpha-T into blood components in hyperlipidemia. Because these blood components are functionally affected by vitamin E, reduced uptake of alpha-T may be relevant to the pathogenesis of atherosclerosis.

Adult↗
PubMed2005

Noncompetitive plasma biokinetics of deuterium-labeled natural and synthetic alpha-tocopherol in healthy men with an apoE4 genotype.

Previous studies comparing the biokinetics of deuterated natural (RRR) and synthetic (all-rac) alpha-tocopherol (vitamin E) used a simultaneous ingestion or competitive uptake approach and reported relative bioavailability ratios close to 2:1, higher than the accepted biopotency ratio of 1.36:1. The aim of the current study was to compare the biokinetics of deuterated natural and synthetic vitamin E using a noncompetitive uptake model both before and after vitamin E supplementation in a distinct population. Healthy men (n = 10) carrying the apolipoprotein (apo)E4 genotype completed a randomized crossover study, comprised of two 4-wk treatments with 400 mg/d (RRR-alpha-tocopheryl and all-rac-alpha-tocopheryl acetate) with a 12-wk washout period between treatments. Before and after each treatment period, the subjects consumed a capsule containing 150 mg deuterated alpha-tocopheryl acetate in either the RRR or all-rac form depending on their treatment regimen. Blood was obtained up to 48 h after ingestion, and tocopherols analyzed by LC/MS. After deuterated all-rac administration, plasma deuterated tocopherol maximum concentrations and area under the concentration vs. time curves (AUC) were lower than those following RRR administration. The RRR:all-rac ratios determined from the deuterated biokinetic profiles (maximum concentration; C(max)) and AUCs were 1.35:1 +/- 0.17 and 1.33:1 +/- 0.18, respectively. The 4-wk supplementation with either RRR or all-rac significantly increased plasma alpha-tocopherol concentrations (P < 0.001), but decreased the plasma response to newly absorbed deuterated RRR or all-rac alpha-tocopherol. Using a noncompetitive uptake approach, the relative bioavailability of natural to synthetic vitamin E in apoE4 males was close to the currently accepted biopotency ratio of 1.36:1.

Apolipoprotein E4↗
PubMed2004

The absorption of vitamin E is influenced by the amount of fat in a meal and the food matrix.

Vitamin E absorption requires the presence of fat; however, limited information exists on the influence of fat quantity on optimal absorption. In the present study we compared the absorption of stable-isotope-labelled vitamin E following meals of varying fat content and source. In a randomised four-way cross-over study, eight healthy individuals consumed a capsule containing 150 mg (2)H-labelled RRR-alpha-tocopheryl acetate with a test meal of toast with butter (17.5 g fat), cereal with full-fat milk (17.5 g fat), cereal with semi-skimmed milk (2.7 g fat) and water (0 g fat). Blood was taken at 0, 0.5, 1, 1.5, 2, 3, 6 and 9 h following ingestion, chylomicrons were isolated, and (2)H-labelled alpha-tocopherol was analysed in the chylomicron and plasma samples. There was a significant time (P<0.001) and treatment effect (P<0.001) in (2)H-labelled alpha-tocopherol concentration in both chylomicrons and plasma between the test meals. (2)H-labelled alpha-tocopherol concentration was significantly greater with the higher-fat toast and butter meal compared with the low-fat cereal meal or water (P<0.001), and a trend towards greater concentration compared with the high-fat cereal meal (P=0.065). There was significantly greater (2)H-labelled alpha-tocopherol concentration with the high-fat cereal meal compared with the low-fat cereal meal (P<0.05). The (2)H-labelled alpha-tocopherol concentration following either the low-fat cereal meal or water was low. These results demonstrate that both the amount of fat and the food matrix influence vitamin E absorption. These factors should be considered by consumers and for future vitamin E intervention studies.

Adult↗
PubMed2004

Cigarette smokers have decreased lymphocyte and platelet alpha-tocopherol levels and increased excretion of the gamma-tocopherol metabolite gamma-carboxyethyl-hydroxychroman (gamma-CEHC).

Cigarette smoking is associated with increased oxidative stress and increased risk of degenerative disease. As the major lipophilic antioxidant, requirements for vitamin E may be higher in smokers due to increased utilisation. In this observational study we have compared vitamin E status in smokers and non-smokers using a holistic approach by measuring plasma, erythrocyte, lymphocyte and platelet alpha- and gamma-tocopherol, as well as the specific urinary vitamin E metabolites alpha- and gamma-carboxyethyl-hydroxychroman (CEHC). Fifteen smokers (average age 27 years, smoking time 7.5 years) and non-smokers of comparable age, gender and body mass index (BMI) were recruited. Subjects completed a 7-day food diary and on the final day they provided a 24 h urine collection and a 20 ml blood sample for measurement of urinary vitamin E metabolites and total vitamin E in blood components, respectively. No significant differences were found between plasma and erythrocyte alpha- and gamma-tocopherol in smokers and non-smokers. However, smokers had significantly lower alpha-tocopherol (mean+/-SD, 1.34+/-0.31 micromol/g protein compared with 1.94+/-0.54, P = 0.001) and gamma-tocopherol (0.19+/-0.04 micromol/g protein compared with 0.26+/-0.08, P = 0.026) levels in their lymphocytes, as well as significantly lower alpha-tocopherol levels in platelets (1.09+/-0.49 micromol/g protein compared with 1.60+/-0.55, P = 0.014; gamma-tocopherol levels were similar). Interestingly smokers also had significantly higher excretion of the urinary gamma-tocopherol metabolite, gamma-CEHC (0.49+/-0.25mg/g creatinine compared with 0.32+/-0.16, P = 0.036) compared to non-smokers, while their alpha-CEHC (metabolite of alpha-tocopherol) levels were similar. There was no significant difference between plasma ascorbate, urate and F2-isoprostane levels. Therefore in this population of cigarette smokers (mean age 27 years, mean smoking duration 7.5 years), alterations to vitamin E status can be observed even without the more characteristic changes to ascorbate and F2-isoprostanes. We suggest that the measurement of lymphocyte and platelet vitamin E may represent a valuable biomarker of vitamin E status in relation to oxidative stress conditions.

Adult↗
PubMed2004

In silico search for single nucleotide polymorphisms in genes important in vitamin E homeostasis.

Large inter-individual variation exists in the response to vitamin E supplementation, and this may influence the outcome of human studies. It is our hypothesis that genetic heterogeneity is an important determinant of vitamin E homeostasis. Therefore we have performed an in silico search for single nucleotide polymorphisms (SNPs) associated with genes involved in vitamin E homeostasis. Based on function, the following genes were considered as candidates for vitamin E heterogeneity: c-tocopherol transfer protein (TTPA), tocopherol associated protein (TAP), lipoprotein lipase (LPL), multidrug resistance protein 2 (MDR-2), pregnane X receptor (PXR) and members of the cytochrome P450 family (CYP). Searches for coding SNPs were initiated from web based programs of the National Center for Biotechnology Information (NCBI). SNP frequencies were calculated by dividing the number of annotated coding SNPs by the number of base pairs in the open reading frame. Genes for TTPA, TAP and CYP3A5 had calculated SNP frequencies between 503 and 837 base pairs per coding SNP (bp/cSNP) and so are not highly polymorphic. In contrast, cSNP frequencies in LPL, MRP2, PXR, CYP3A4 and CYP4F2 were in the range of 100 bp/cSNP and so are highly polymorphic. Thus proteins involved in specific vitamin E binding are not highly polymorphic, may not influence inter-individual variation and so may not be good candidates for population studies. Proteins involved in drug/lipid metabolism which indirectly influence vitamin E status are highly polymorphic, are likely to influence inter-individual variation and so are good candidates for population studies. We suggest that future studies are aimed at addressing the role of such SNPs in vitamin E homeostasis.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2004

Physiological factors influencing vitamin E biokinetics.

Limited information is available on factors that can influence vitamin E bioavailability. In several studies we have investigated the influence of dietary, biochemical, and genetic factors on vitamin E biokinetics. In these studies, subjects ingested a capsule containing 150 mg deuterated RRR-alpha-tocopheryl acetate, blood was taken up to 48 hr, and tocopherols were analyzed by liquid chromatography and mass spectroscopy. There was significantly greater plasma-labeled alpha-tocopherol concentrations when the capsule was consumed with a high-fat meal (17.5 g) versus a low-fat meal (2.7 g), and there was also a difference between a high-fat toast and butter and a cereal with full-fat milk meal (both 17.5 g fat), indicating that both the amount of fat and food matrix is important for vitamin E absorption. Dyslipidemic subjects displayed a reduced plasma uptake of newly absorbed alpha-tocopherol, and differences were also apparent in individual lipoproteins. A decreased uptake of labeled alpha-tocopherol was also observed in erythrocytes, platelets, and lymphocytes of dyslipidemics. Following vitamin E supplementation (400 mg/day, 4 weeks), the uptake of newly absorbed alpha-tocopherol was decreased, presumably because of saturation of alpha-tocopherol transfer protein. We also found that apoE3 subjects displayed a considerably reduced uptake of newly absorbed labeled alpha-tocopherol compared to apoE4 subjects, which may be a consequence of the reduced low-density lipoprotein catabolic rate in these subjects. Taken together, these data show that several physiological factors influence the uptake of newly absorbed alpha-tocopherol, and that this is an important consideration in the design of future vitamin E supplementation studies.

Apolipoproteins E↗
PubMed2003

Development of a liquid chromatographic time-of-flight mass spectrometric method for the determination of unlabelled and deuterium-labelled alpha-tocopherol in blood components.

A method is described for the analysis of deuterated and undeuterated alpha-tocopherol in blood components using liquid chromatography coupled to an orthogonal acceleration time-of-flight (TOF) mass spectrometer. Optimal ionisation conditions for undeuterated (d0) and tri- and hexadeuterated (d3 or d6) alpha-tocopherol standards were found with negative ion mode electrospray ionisation. Each species produced an isotopically resolved single ion of exact mass. Calibration curves of pure standards were linear in the range tested (0-1.5 microM, 0-15 pmol injected). For quantification of d0 and d6 in blood components following a standard solvent extraction, a stable-isotope-labelled internal standard (d3-alpha-tocopherol) was employed. To counter matrix ion suppression effects, standard response curves were generated following identical solvent extraction procedures to those of the samples. Within-day and between-day precision were determined for quantification of d0- and d6-labelled alpha-tocopherol in each blood component and both averaged 3-10%. Accuracy was assessed by comparison with a standard high-performance liquid chromatography (HPLC) method, achieving good correlation (r(2) = 0.94), and by spiking with known concentrations of alpha-tocopherol (98% accuracy). Limits of detection and quantification were determined to be 5 and 50 fmol injected, respectively. The assay was used to measure the appearance and disappearance of deuterium-labelled alpha-tocopherol in human blood components following deuterium-labelled (d6) RRR-alpha-tocopheryl acetate ingestion. The new LC/TOFMS method was found to be sensitive, required small sample volumes, was reproducible and robust, and was capable of high throughput when large numbers of samples were generated.

Adult↗