Vitamin E reduces cardiovascular disease in individuals with diabetes mellitus and the haptoglobin 2-2 genotype.
AIMS: Individuals with both diabetes mellitus (DM) and the Haptoglobin (Hp) 2-2 genotype are at increased risk of cardiovascular disease. As the antioxidant function of the Hp 2-2 protein is impaired, we sought to test the pharmacogenomic hypothesis that antioxidant vitamin E supplementation would provide cardiovascular protection to Hp 2-2 DM individuals. MATERIALS & METHODS: We determined the Hp genotype on DM participants from two trials (HOPE and ICARE) and assessed the effect of vitamin E by Hp genotype on their common prespecified outcome, the composite of stroke, myocardial infarction and cardiovascular death. Data was analyzed with a fixed-effect model. These results were input into a simulation model, the Evidence Based Medicine Integrator, in order to estimate their long-term implications in a real-world population from Kaiser Permanente (CA, USA). RESULTS: Meta-analysis of the two trials demonstrated a significant overall reduction in the composite end point in Hp 2-2 DM individuals with vitamin E (odds ratio: 0.58; 95% CI: 0.40-0.86; p = 0.006). There was a statistically significant interaction between the Hp genotype and vitamin E on the composite end point. In these trials, Hp typing of 69 DM individuals and treating those with the Hp 2-2 with vitamin E prevented one myocardial infarct, stroke or cardiovascular death. Lifelong administration of vitamin E to Hp 2-2 DM individuals in the Kaiser population would increase their life expectancy by 3 years. CONCLUSION: A pharmacogenomic strategy of screening DM individuals for the Hp genotype and treating those with Hp 2-2 with vitamin E appears to be highly clinically effective.
Pharmacogenomics. 2010 May;11(5):675-84
Evaluation of plasma non-enzymatic antioxidants in breast cancer etiology.
OBJECTIVE: Oxidative stress has emerged as a major etiological factor for breast cancer. Diet derived antioxidants play an important role against oxidative stress and the aim of the present study was to examine roles of non-enzymatic antioxidants in breast cancer in India. METHODS: Plasma non-enzymatic antioxidants; beta-carotene, vitamin A, vitamin E and vitamin C were analyzed spectrophotometrically from 70 healthy female controls, 30 patients with benign breast diseases (BBD) and 125 untreated breast cancer patients (BCPT). RESULTS: Plasma vitamin C levels were significantly lower in patients with BBD as compared to the controls (p= 0.043). Plasma beta-carotene, vitamin E and vitamin C levels were significantly lower in BCPT as compared to the controls (p= 0.0001, p= 0.040 and p= 0.0001, respectively). Plasma vitamin A levels were significantly higher in patients with BBD and BCPT as compared to the controls (p= 0.0001 and p= 0.0001; respectively) and in BCPT as compared to patients with BBD (p= 0.030). ROC curve analysis revealed that plasma beta-carotene and vitamin A could significantly discriminate between controls and patients with BBD (p= 0.016 and p= 0.000; respectively). Plasma beta-carotene, vitamin A, vitamin E and vitamin C could significantly discriminate between controls and BCPT (p= 0.000, p= 0.000, p= 0.001and p= 0.001, respectively). Plasma vitamin E levels could significantly discriminate between patients with BBD and BCPT (p= 0.055). Odds ratio analysis revealed that, increasing levels of plasma beta-carotene, vitamin E and vitamin C were significantly associated with decreased risk of breast cancer (p= 0.0001, p= 0.003, and p= 0.0001; respectively), whereas, increased risk was linked to plasma vitamin A (p= 0.001). CONCLUSIONS: The trends of the current study provide interesting clues to the etiology of breast cancer and suggest significance of interplay of non-enzymatic antioxidants in breast cancer. Further in-depth study is warranted to elucidate role of these antioxidants as a preventive measure.
Asian Pac J Cancer Prev. 2009 Jan-Mar;10(1):91-6
Vitamin E: an overview of major research directions.
During the last 90 years since the discovery of vitamin E, research has focused on different properties of this molecule, the focus often depending on the specific techniques and scientific knowledge present at each time. Originally discovered as a dietary factor essential for reproduction in rats, vitamin E has revealed in the meantime many more important molecular properties, such as the scavenging of reactive oxygen and nitrogen species with consequent prevention of oxidative damage associated with many diseases, or the modulation of signal transduction and gene expression in antioxidant and non-antioxidant manners. Research over the last 30 years has also resolved the biosynthesis and occurrence of vitamin E in plants, the proteins involved in the cellular uptake, tissue distribution and metabolism, and defined a congenital recessive neurological disease, ataxia with vitamin E deficiency (AVED), characterized by impaired enrichment of alpha-tocopherol in plasma as a result of mutations in the liver alpha-tocopherol transfer gene. This review is giving a brief introduction about vitamin E by following the major research directions since its discovery with a historical perspective.
Mol Aspects Med. 2007 Oct-Dec;28(5-6):400-22
High plasma levels of vitamin E forms and reduced Alzheimer’s disease risk in advanced age.
In this study we investigated the association between plasma levels of eight forms of vitamin E and incidence of Alzheimer’s disease (AD) among oldest-old individuals in a population-based setting. A dementia-free sample of 232 subjects aged 80+ years, derived from the Kungsholmen Project, was followed-up to 6 years to detect incident AD. Plasma levels of vitamin E (alpha-, beta-, gamma, and delta-tocopherol; alpha-, beta-, gamma-, and delta-tocotrienol) were measured at baseline. Vitamin E forms-AD association was analyzed with Cox proportional hazard model after adjustment for several potential confounders. Subjects with plasma levels of total tocopherols, total tocotrienols, or total vitamin E in the highest tertile had a reduced risk of developing AD in comparison to persons in the lowest tertile. Multi-adjusted hazard ratios (HRs) and 95% confidence interval (CI) were 0.55 (0.32-0.94) for total tocopherols, 0.46 (0.23-0.92) for total tocotrienols, and 0.55 (0.32-0.94) for total vitamin E. When considering each vitamin E form, the risk of developing AD was reduced only in association with high plasma levels of beta-tocopherol (HR: 0.62, 95% CI 0.39-0.99), whereas alpha-tocopherol, alpha- tocotrienol, and beta-tocotrienol showed only a marginally significant effect in the multiadjusted model [HR (95% CI): alpha-tocopherol: 0.72 (0.48-1.09); alpha-tocotrienol: 0.70 (0.44-1.11); beta-tocotrienol: 0.69 (0.45-1.06)]. In conclusion, high plasma levels of vitamin E are associated with a reduced risk of AD in advanced age. The neuroprotective effect of vitamin E seems to be related to the combination of different forms, rather than to alpha-tocopherol alone, whose efficacy in interventions against AD is currently debated.
J Alzheimers Dis. 2010;20(4):1029-37
Cancer-preventive activities of tocopherols and tocotrienols.
The cancer-preventive activity of vitamin E has been studied. Whereas some epidemiological studies have suggested a protective effect of vitamin E against cancer formation, many large-scale intervention studies with alpha-tocopherol (usually large doses) have not demonstrated a cancer-preventive effect. Studies on alpha-tocopherol in animal models also have not demonstrated robust cancer prevention effects. One possible explanation for the lack of demonstrable cancer-preventive effects is that high doses of alpha-tocopherol decrease the blood and tissue levels of delta-tocopherols. It has been suggested that gamma-tocopherol, due to its strong anti-inflammatory and other activities, may be the more effective form of vitamin E in cancer prevention. Our recent results have demonstrated that a gamma-tocopherol-rich mixture of tocopherols inhibits colon, prostate, mammary and lung tumorigenesis in animal models, suggesting that this mixture may have a high potential for applications in the prevention of human cancer. In this review, we discuss biochemical properties of tocopherols, results of possible cancer-preventive effects in humans and animal models and possible mechanisms involved in the inhibition of carcinogenesis. Based on this information, we propose that a gamma-tocopherol-rich mixture of tocopherols is a very promising cancer-preventive agent and warrants extensive future research.
Carcinogenesis. 2010 Apr;31(4):533-42
Vitamin E forms in Alzheimer’s disease: a review of controversial and clinical experiences.
Vitamin E is a collective term for eight naturally occurring compounds, four tocopherols (alpha-, beta-, gamma-, and delta-) and four tocotrienols (alpha-, beta-, gamma-, and delta-). Although it is the major form of vitamin E in US diets, gamma-tocopherol receives little attention when compared to alpha-tocopherol, which is generally found in supplements and most studied for its effects on progression of cognitive impairment. Many clinical trials had been conducted with vitamin E and neurodegenerative disorders, with controversial results, including a recent study which disproves the benefit of vitamin E for Mild Cognitive Impairment and Alzheimer’s Disease. This study examined the alpha-tocopherol supplement instead of gamma-tocopherol. Gamma-tocopherol has been found to be more effective in scavenging free radicals and nitrogen oxygen species that cause inflammation; both of these are components of neurodegenerative disorders. Secondly, the use of alpha-tocopherol supplements significantly reduces serum gamma-tocopherol, and this may have important biological effects. Therefore, any potential health benefits of alpha-tocopherol supplements may be offset by deleterious changes in the bioavailability of other forms of tocopherols and tocotrienols. This might account for the null effects of alpha tocopherol supplementation in Mild Cognitive Impairment and Alzheimer’s Disease.
Crit Rev Food Sci Nutr. 2010 May;50(5):414-9
Undercarboxylated osteocalcin is a biomarker of carotid calcification in patients with essential hypertension.
The development of vascular calcification is an active, highly regulated process with similarities to bone formation. Osteocalcin (OC), a vitamin K-dependent protein expressed by osteoblasts, contains 3 gamma-carboxyglutamic acid residues derived from the vitamin K-dependent posttranslational modification of glutamic acid residues. Circulating undercarboxylated OC (ucOC) is increased in vitamin K deficiency and serum ucOC is reported to be a clinical marker of vitamin K status. Vitamin K deficiency is associated with vascular calcification as well as osteoporosis. We evaluated the relationship between ucOC and carotid artery calcification in 92 patients with essential hypertension. Ultrasound of the common carotid artery was performed to identify vascular calcification and subjects were divided into 2 groups: a calcification (+) group and a calcification (-) group. Serum creatinine and ucOC levels were higher in the calcification (+) group than in the calcification (-) group and serum ucOC correlated with serum creatinine. To identify the independent determinant factor for carotid artery calcification, we applied both ucOC and estimated glomerular filtration rate as independent factors in logistic regression analysis. Serum ucOC was an independent determinant of carotid calcification, suggesting that circulating ucOC may be an important biomarker of carotid artery calcification.
Kidney Blood Press Res. 2010;33(1):66-71
Efficacy of menatetrenone (vitamin K2) against non-vertebral and hip fractures in patients with neurological diseases: meta-analysis of three randomized, controlled trials.
BACKGROUND AND OBJECTIVE: Patients with neurological diseases such as Alzheimer’s disease, stroke and Parkinson’s disease have been reported to have vitamin K deficiency secondary to malnutrition, which increases the risk of non-vertebral and hip fractures. The purpose of the present study was to clarify the efficacy of menatetrenone (vitamin K(2)) against non-vertebral and hip fractures in patients with neurological diseases. METHODS: A literature search was conducted on PubMed from January 1995 to July 2008 to identify randomized controlled trials (RCTs) of use of menatetrenone against non-vertebral and hip fractures in patients with neurological diseases. A meta-analysis of all RCTs meeting these criteria was then performed. RESULTS: Three RCTs of patients with Alzheimer’s disease (n = 178, mean age 78 years), stroke (n = 99, mean age 66 years) and Parkinson’s disease (n = 110, mean age 72 years) met the criteria for meta-analysis. These RCTs did not include placebo controls but did have non-treatment controls. According to the meta-analysis, the overall relative risks (95% confidence intervals) for non-vertebral and hip fractures with menatetrenone treatment compared with non-treatment were 0.13 (0.05, 0.35) and 0.14 (0.05, 0.43), respectively, in patients with neurological diseases. No severe adverse events were reported with menatetrenone treatment. CONCLUSION: The present meta-analysis of three RCTs suggests that there is efficacy for menatetrenone treatment against non-vertebral and hip fractures among patients with neurological diseases. Further larger placebo-controlled trials are needed to confirm the results of the present study.
Clin Drug Investig. 2009;29(7):471-9
Vitamin K supplementation and progression of coronary artery calcium in older men and women.
BACKGROUND: Coronary artery calcification (CAC) is an independent predictor of cardiovascular disease. A preventive role for vitamin K in CAC progression has been proposed on the basis of the properties of matrix Gla protein (MGP) as a vitamin K-dependent calcification inhibitor. OBJECTIVE: The objective was to determine the effect of phylloquinone (vitamin K1) supplementation on CAC progression in older men and women. DESIGN: CAC was measured at baseline and after 3 y of follow-up in 388 healthy men and postmenopausal women; 200 received a multivitamin with 500 microg phylloquinone/d (treatment), and 188 received a multivitamin alone (control). RESULTS: In an intention-to-treat analysis, there was no difference in CAC progression between the phylloquinone group and the control group; the mean (+/-SEM) changes in Agatston scores were 27 +/- 6 and 37 +/- 7, respectively. In a subgroup analysis of participants who were > or =85% adherent to supplementation (n = 367), there was less CAC progression in the phylloquinone group than in the control group (P = 0.03). Of those with preexisting CAC (Agatston score > 10), those who received phylloquinone supplements had 6% less progression than did those who received the multivitamin alone (P = 0.04). Phylloquinone-associated decreases in CAC progression were independent of changes in serum MGP. MGP carboxylation status was not determined. CONCLUSIONS: Phylloquinone supplementation slows the progression of CAC in healthy older adults with preexisting CAC, independent of its effect on total MGP concentrations. Because our data are hypothesis-generating, further studies are warranted to clarify this mechanism. This trial was registered at clinicaltrials.gov as NCT00183001.
Am J Clin Nutr. 2009 Jun;89(6):1799-807
Effects of vitamin K on bone mass and bone metabolism.
Vitamin K is involved in blood coagulation and in bone metabolism via the carboxylation of glutamate residues in (hepatic) blood coagulation factors and (osteoblastic) bone proteins. The bioavailability of nutritional vitamin K depends on the type of food, the dietary fat content, the length of the aliphatic side chain in the K-vitamer and probably also the genetically determined polymorphism of apolipoprotein E. Although undercarboxylation of blood coagulation factors is very rare, undercarboxylated osteocalcin (bone Gla-protein) is frequently found in postmenopausal women. Supplementation of these women with extra vitamin K causes the markers for bone formation to increase. In parallel, a decrease of the markers for bone resorption is frequently seen. Insufficient data are available to conclude that the regular administration of vitamin K concentrates will reduce the loss of bone mass in white women at risk for developing postmenopausal osteoporosis.
J Nutr. 1996 Apr;126(4 Suppl):1187S-91S