Selenium vitaminology: The connection between selenium,vitamin C,vitamin E,and ergothioneine

Selenium is connected to three small molecule antioxidant compounds, ascorbate, α-tocopherol, and ergothioneine. Ascorbate and α-tocopherol are true vitamins, while ergothioneine is a “vitamin-like” compound. Here we review how selenium is connected to all three. Selenium and vitamin E work together as a team to prevent lipid peroxidation. Vitamin E quenches lipid hydroperoxyl radicals and the resulting lipid hydroperoxide is then converted to the lipid alcohol by selenocysteine-containing glutathione peroxidase. Ascorbate reduces the resulting α-tocopheroxyl radical in this reaction back to α-tocopherol with concomitant production of the ascorbyl radical. The ascorbyl radical can be reduced back to ascorbate by selenocysteine-containing thioredoxin reductase. Ergothioneine and ascorbate are both water soluble, small molecule reductants that can reduce free radicals and redox-active metals. Thioredoxin reductase can reduce oxidized forms of ergothioneine. While the biological significance of this is not yet realized, this discovery underscores the centrality of selenium to all three antioxidants.     

Goldilocks,vitamin D and sarcoidosis

While low levels of vitamin D can increase the risk for osteoporosis, excessive amounts of vitamin D may also be problematic. Hypercalcemia and hypercalcuria due to increased vitamin D activity occur in a significant proportion of sarcoidosis patients. Saidenberg-Kermanac’h and colleagues compared vitamin D levels with bone fragility fractures in their sarcoidosis clinic. They found that a 25-(OH) vitamin D level between 10 and 20 ng/ml was associated with the lowest risk of bone fractures and paradoxically higher levels increased the risk of bone fractures. Using less vitamin D supplementation may simultaneously lower the risk for bone fracture and hypercalcemia in sarcoidosis.In the previous issue, Saidenberg-Kermanac’h and colleagues provide more information regarding the complexity of vitamin D activity in sarcoidosis [1]. A few years ago, vitamin D was declared the nutrient of the decade. This was heady stuff for a sterol that was originally felt important only in preventing rickets. Studies have demonstrated its key role in calcium absorption and bone growth. Beyond that, vitamin D has been considered an important sterol in various aspects of health. Low levels of vitamin D have been associated with increased risk for cancer, type 2 diabetes, and heart disease.Most of these observations have been based on measurements of 25-(OH)-vitamin D3 (ergocalcitrol). This sterol is converted by 1-alpha hydroxylase to 1,25-(OH)2-vitamin D3 (calcitrol), the active form of vitamin D. This conversion occurs in the kidney and patients with chronic renal failure require calcitrol replacement.In tuberculosis, vitamin D supplementation has been recommended in patients because vitamin D is crucial in the granulomatous reaction against the organism. However, what may be good for tuberculosis eradication may not be good for sarcoidosis. It has been noted that excessive amounts of vitamin D are associated with a worse clinical outcome in sarcoidosis [2]. In granulomas, there may be increased activity of 1-alpha hydroxylase. As part of the Th-1 immune response, calcitrol has a paracrine effect within the granuloma. In some cases, this leads to excessive calcitrol, resulting in hypercalcuria or hypercalcemia [3]. At least 10% of sarcoidosis patients have hypercalcemia, half of whom can develop associated renal dysfunction [3,4]. In some cases, hypercalcemic renal failure can be reversed by simply withdrawing vitamin D supplementation [3]. There are case reports of excessive vitamin D replacement leading to hypercalcemia in patients with mycobacterial infections [5].The sarcoidosis patient may be treated with glucocorticoids, sometimes for years. Obviously, long-term glucocorticoid administration places the patient at risk for developing osteoporosis [6,7]. In rheumatoid arthritis, patients undergoing prolonged glucocorticoid treatment are recommended to receive calcium and vitamin D replacement [8]. While this is the cornerstone of prevention of osteoporosis, the role of calcium and vitamin D replacement in sarcoidosis remains unclear [9].Into this quandary comes the study by Saidenberg-Kermanac’h and colleagues reported in the previous issue of Arthritis Research & Therapy[1]. After studying a large cohort of sarcoidosis patients from their clinic, the authors found that fragility fractures occurred in nearly a quarter of them. The fracture risk was increased for those treated with corticosteroids. Although low levels of ergocalcitrol was an independent risk for osteoporosis, ironically high levels of ergocalcitrol were also associated with an increased risk for osteoporosis. They found that ergocalcitrol levels of 10 to 20 ng/ml was associated with the lowest fracture risk for patients. This J shaped risk for bone fragility has been noted in non-sarcoidosis patients, although the proposed target levels are higher for these patients [10]. For the clinician treating sarcoidosis, one has to balance not only the risk for osteoporosis, but also the risk for hypercalcemia and renal failure (Figure 1).Open in a separate windowFigure 1Schematic depicting vitamin D metabolism in the body from ergocalcitrol to calcitrol. The conversion is enhanced by increased activity of 1-alpha hydroxylase activity in the granuloma of sarcoidosis patients. The untoward consequences of low or high vitamin D activity are summarized at the bottom of the figure.One possible explanation for the lower ideal ergocalcitrol level in sarcoidosis is the enhanced activity of 1-alpha hydroxylase in sarcoidosis granulomas. The authors did not provide information regarding calcitrol levels in their patients. The proportion of calcitrol to ergocalcitrol appears to be higher in sarcoidosis compared to non-sarcoidosis conditions. In one study of 270 sarcoidosis patients, 80% had low ergocalcitrol levels, but less than 1% had low calcitrol levels. In fact, that study found that 10% of patients had elevated calcitrol levels [3]. Those with elevated calcitrol were more likely to have a history of hypercalcemia or hypercalcuria. Higher levels of calcitrol have been associated with more advanced pulmonary sarcoidosis [2].The other potential benefits of vitamin D replacement in sarcoidosis are unclear. Should sarcoidosis patients with low ergocalcitrol but normal calcitrol levels be prescribed vitamin D supplementation to reduce their risk for cancer and type 2 diabetes? If so, do they increase their risk for hypercalcemia or hypercalcuria? Could this increased vitamin D intake raise the functional level of vitamin D even higher and therefore increase the risk for osteoporosis?To paraphrase Goldilocks, one does not want too little or too much vitamin D. You want just the right amount.     

Dreaming,fenfluramine, and vitamin C.

The effect of increasing doses of fenfluramine on dream patterns was studied in 20 patients receiving a reducing diet with or without a controlled dietary intake of vitamin C daily. The dream pattern was unchanged in six patients and dreams disappeared in another who normally dreamed often. In 13 patients dreams increased in frequency and intensity, and in five the dreams assumed frightening proportions. There was a significant straight-line relation between response and the size of the dose. When placebo tablets were given to four patients their dreams disappeared or assumed their pretreatment normal pattern. Absence of vitamin C from the diet did not significantly affect the dream pattern. That fenfluramine has dose-related cerebral effects should be remembered in patients with a history of mental illness.     

Levels of plasma vitamin E,vitamin C,TBARS, and cholesterol in male patients with colorectal tumors

Vitamin E and vitamin C are involved in the defense of the body against free radical and reactive oxygen molecule induced damage. The best characterized biological damage caused by radicals is known as lipid peroxidation. Free radical formation is known to play a major role in the development of cancer. In this study, we measured plasma levels of thiobarbituric acid reactive substances (TBARS) as a marker of lipid peroxidation, cholesterol, and vitamins E and C as antioxidants in male patients with colorectal tumors (n = 20, 54.5 ± 8.3 years). The patients had significantly higher plasma TBARS levels than age-matched healthy subjects (p < 0.001). Plasma vitamin C levels were significantly lower in the patients compared to the healthy subjects (p < 0.001). On the other hand, plasma vitamin E levels in the patients were similar to those of healthy subjects. Plasma cholesterol levels were also found to be significantly elevated in patients with colorectal tumors (p < 0.001). Our results suggest that there is an imbalance between oxidant and antioxidant status in tumor genesis.     

Production of antioxidant vitamins, beta-carotene, vitamin C, and vitamin E, by two-step culture of Euglena gracilis Z

Euglena gracilis Z is one of the few microorganisms which simultaneously produces antioxidant vitamins such as beta-carotene and vitamins C and E. Photoheterotrophically cultured E. gracilis Z produced larger levels of biomass but with a lower content of antioxidant vitamins than photoautotrophically grown cultures. For efficient production of these vitamins, a two-step culture was performed. Cells were grown photoheterotrophically and then transferred to photoautotrophic conditions. When E. gracilis Z cells were grown in fed-batch culture under photoheterotrophic conditions, their density reached 19 g/L after 145 h. Subsequent transfer of these cells to photoautotrophic conditions increased vitamin content, enhancing the total vitamin yields, which were 71.0 mg/L of beta-carotene, 30.1 mg/L of vitamin E, and 86.5 mg/L of vitamin C. (c) 1997 John Wiley & Sons, Inc.     

Photoprotective potential of lycopene,beta-carotene,vitamin E,vitamin C and carnosic acid in UVA-irradiated human skin fibroblasts

The photoprotective potential of the dietary antioxidants vitamin C, vitamin E, lycopene, beta-carotene, and the rosemary polyphenol, carnosic acid, was tested in human dermal fibroblasts exposed to ultraviolet-A (UVA) light. The carotenoids were prepared in special nanoparticle formulations together with vitamin C and/or vitamin E. Nanoparticle formulations, in contrast to dimethylsulphoxide, stablized lycopene in the cell culture medium and allowed efficient cellular uptake. The presence of vitamin E in the formulation further increased the stability and cellular uptake of lycopene. UVA irradiation of the human skin fibroblasts led to a 10-15-fold rise in metalloproteinase 1 (MMP-1) mRNA. This rise was suppressed in the presence of low microM concentrations of vitamin E, vitamin C, or carnosic acid but not with beta-carotene or lycopene. Indeed, in the presence of 0.5-1.0 microM beta-carotene or lycopene, the UVA-induced MMP-1 mRNA was further increased by 1.5-2-fold. This increase was totally suppressed when vitamin E was included in the nanoparticle formulation. Heme-oxygenase 1 (HO-1) mRNA expression was strongly induced by UVA irradiation but none of the antioxidants inhibited this effect at the concentrations used in this study. Indeed, beta-carotene or lycopene (0.5-1.0 microM) led to a further 1.5-fold rise in the UVA-induced HO-1 mRNA levels. In conclusion, vitamin C, vitamin E, and carnosic acid showed photoprotective potential. Lycopene and beta-carotene did not protect on their own but in the presence of vitamin E, their stability in culture was improved and the rise in MMP-1 mRNA expression was suppressed, suggesting a requirement for antioxidant protection of the carotenoids against formation of oxidative derivatives that can influence the cellular and molecular responses.     

Protective role of supplemental vitamin E and selenium on lipid peroxidation, vitamin E, vitamin A, and some mineral concentrations of Japanese quails reared under heat stress

This study was conducted to determine the effects of vitamin E and selenium (Se) on lipid peroxidation (MDA), serum and liver concentration of antioxidant vitamins, and some minerals of Japanese quails reared under heat stress (34°C). One hundred twenty 10-d-old Japanese qualis (60 males, 60 females) were randomly assigned to 4 treatment groups, 3 replicates of 10 birds each. The experiment was designed in a 2×2 factorial arrangement using two levels of vitamin E (125 and 250 mg/kg of diet) and two levels of selenium (0.1 and 0.2 mg/kg of diet). Greater dietary vitamin E and selenium inclusions resulted in a greater (p=0.001) serum vitamin E and vitamin A, but lower (p=0.001) MDA concentrations. Liver vitamin E and vitamin A concentrations increased (p=0.001) and MDA concentrations decreased (p=0.001) when both dietary vitamin E and selenium increased. No interactions between vitamin E and selenium were detected (p≥0.11) for any parameters. Increasing both dietary vitamin E and selenium caused an increase in serum concentrations of Fe and Zn (p=0.001), but a decrease in serum concentration of Cu (p=0.001). Results of the present study showed that dietary vitamin E and selenium have synergistic effects and that supplementing a combination of dietary vitamin E (250 mg/kg of diet) and selenium (0.2 mg/kg of diet) offers a good management practice to reduce heat stress-related depression in performance of Japanese quails.     

Hyperlipidemia and reproductive failure in captive-reared alligators: vitamin E, vitamin A, plasma lipids, fatty acids, and steroid hormones

Blood samples were collected from 26 captive-reared alligators (25 females; one male) and 12 (seven females and five males) wild "nuisance" alligators collected by wildlife personnel in south Louisiana in May 1995. The captive alligators, hatched from artificially incubated eggs in 1972-1973, had received vitamin E supplements during the 3 weeks before the blood sample was collected. Each sample was analyzed for vitamin E (alpha-tocopherol), vitamin A (retinol), total lipid, triacylglycerol, phospholipid, cholesterol, cholesteryl ester, free fatty acids, steroid hormones and a standard clinical blood panel. The fatty acid composition of the plasma lipid fraction was also analyzed. Results indicated that 18 of the captive females and three of the seven wild females were undergoing vitellogenesis, i.e. had elevated plasma estradiol and elevated plasma calcium. Vitellogenic females had higher vitamin E than non-vitellogenic females (77.4 microg/ml vs. 28.6 microg/ml in captive females; 24.0 microg/ml vs. 21 microg/ml in wild females). Plasma retinol was similar in all groups, ranging from 0.5 to 1.4 microg/ml and close to values reported in birds. All lipid fractions, with the exception of cholesteryl ester, were higher in captive alligators than in wild alligators. There were also significant differences in the fatty acid composition of wild and captive alligators. Plasma eicosapentaenoic and docasahexaenoic acid were higher in wild than in captive alligators, whereas linoleic was higher in captive than in wild.     

Carotenoids,vitamin A,and vitamin E concentrations during egg development in panther chameleons (Furcifer pardalis)

Insects are known to be poor sources of preformed vitamin A, leading to the speculation that insectivorous species, including reptiles, may be able to convert carotenoid precursors to meet dietary requirements for this nutrient. This study was conducted to indirectly evaluate carotenoid and vitamin A metabolism in the panther chameleon (Furcifer pardalis). Eggs were obtained from females in Madagascar that were yolked either early or later in the breeding season, and carotenoid (α‐ and β‐carotene, cryptoxanthin, lutein/zeaxanthin, and lycopene), vitamin A, and vitamin E concentrations were measured in egg contents in early, middle, or late embryonic development. An overall trend of decreased nutrient concentration as eggs matured (from egg period 1 (yolks) to egg period 3 (embryos)) was seen within both clutch groups. The season of clutch deposition was a significant influence on egg weight, α‐carotene, and lutein/zeaxanthin concentrations, but on no other nutrients. Chameleon yolks contained considerably higher levels of carotenoids than levels previously reported from two viviparous lizard species, and β‐carotene concentrations were of the same magnitude as reported in grazing tortoises. β‐Carotene and β‐cryptoxanthin were the predominant carotenoids in yolk and embryos, comprising about 95% of total carotenoids detected. Measurable concentrations of retinol at all stages of egg development in the chameleons suggests effective conversion from carotenoid precursors, with concentrations similar to those measured in other lizard eggs. Information from eggs obtained in native habitats may provide baseline data on nutrient interactions to improve and optimize captive dietary management; preliminary data suggest that micronutrient environments may vary over the protracted breeding season, with possible implications for embryo health and survival. Zoo Biol 21:295–303, 2002. © 2002 Wiley‐Liss, Inc.     

Effect of simultaneous administration of vitamin C, L-cysteine and vitamin E on the melanogenesis

The effect of simultaneous administration of vitamin C (ascorbic acid), L-cystein (Cys) and vitamin E (tocopherol) on the melanogenesis in vivo and in vitro was studied. Forty-eight brownish guinea pigs were divided into 4 groups as follows: VC group, VC+Cys group, VC+Cys+VE group and control group. They were given these vitamins by oral administration every day. UV-B exposure (0.384 J/cm2) on their depleted back skin was done at the day 8, 10, 12, 15 17 and 19. After UV-B irradiation, vitamins were administrated further 3 weeks. The luminosity score was measured using a Color Reader CR-11 (Minolta, Co) and the numbers of DOPA-positive melanocytes of their back skin were counted. B16 melanoma cells were incubated with VC, N-acetyl cystein (NAC) and VE. After 4 days of incubation, cells were harvested. The melanin contents and the tyrosinase activities in cells were measured. The luminosity score in the VC+VE+Cys group was higher than those in the other groups. The numbers of DOPA-positive melanocytes of guinea pigs treated with VC, VE and Cys were significantly decreased compared with those in VC group. In B16 melanoma cells, simultaneous treatment of VC, VE and NAC was the most effective to decrease the melanin contents and to inhibit tyrosinase activity.     

Microcystin-induced 8-hydroxydeoxyguanosine in DNA and its reduction by melatonin, vitamin C, and vitamin E in mice

Microcystin LR (MC-LR), a liver-specific toxin synthesized by Microcystis aeruginosa, was investigated. MC-LR initiated reactive oxygen species formation followed by damaging DNA and some other cellular components. We investigated the ability of MC-LR to induce oxidative DNA damage by examining the formation of 8-hydroxydeoxyguanosine (8-OH-dG) using HPLC with electrochemical detection. Melatonin, vitamin C (ascorbate), and vitamin E (as Trolox), all of which are free radical scavengers, markedly inhibited the formation of 8-OH-dG in a concentration-dependent manner. The concentration that reduced DNA damage by 50% (IC₅₀) was 0.55, 31.4, and 36.8 μM for melatonin, ascorbate, and Trolox, respectively. The results show that melatonin is 60-and 70-fold more effective than vitamin C or vitamin E, respectively, in reducing oxidative DNA damage. These findings are consistent with the conclusion that melatonin’s highly protective effect against microcystin toxicity relates, at least in part, to its direct hydroxyl radical scavenging ability. Published in Russian in Biokhimiya, 2006, Vol. 71, No. 10, pp. 1377–1382.     

Absorption, transport, and tissue delivery of vitamin E

Vitamin E is one of the most abundant lipid-soluble antioxidant agents found in plasma and cells of higher mammals. The uptake, transport and tissue delivery of -tocopherol, a key vitamin E form, involves molecular, biochemical, and cellular processes closely related to overall lipid and lipoprotein homeostasis. This review highlights recent findings that have led to a better understanding of vitamin E transport, including intestinal absorption, hepatic transport, and cellular uptake of -tocopherol in vivo. This new information may be critical for manipulation of vitamin E homeostasis in a variety of oxidative stress-related disease conditions in humans.