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Pathways of vitamin A delivery to the embryo: insights from a new tunable model of embryonic vitamin A deficiency.

Circulating retinoids (vitamin A and its derivatives) are found predominantly as retinol bound to retinol-binding protein (RBP), which transports retinol from liver stores to target tissues, or as retinyl ester incorporated in lipoproteins of dietary origin. The transport of retinoids from maternal to fetal circulation is poorly understood, especially under conditions of inadequate dietary vitamin A intake. Here we present RBP-/- mice as a tunable model of embryonic vitamin A deficiency. This model has enabled us to analyze metabolic links between maternal nutrition and retinoid delivery to the fetus. Our data show that retinol-RBP is the primary contributor to fetal development, whereas retinyl ester are largely responsible for accumulation of fetal retinoid stores. Furthermore, these studies indicate the importance of embryonic RBP in distributing vitamin A to certain developing tissues under restrictive diets. We also show differences among developing tissues in their dependency on the embryonic retinol-RBP pathway. Finally, we demonstrate that accumulation of embryonic vitamin A stores does not depend on the expression of RBP in the fetal liver.

Animals↗

Vitamin D metabolism in pregnant rabbits: differences between the maternal and fetal response to administration of large amounts of vitamin D3.

Maternal and fetal metabolism of vitamin D was examined in term pregnant rabbits fed a normal diet and in those supplemented with a large amount of vitamin D3. Term pregnant rabbits (27--30 days of gestation) fed the normal diet showed lower levels of plasma calcium, 25-hydroxyvitamin D3 (250HD3), and 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3] and higher plasma 1 alpha, 25-dihydroxyvitamin D3 [1 alpha, 25-(OH)2D3] levels than age-matched nonpregnant female rabbits. Kidney homogenates from pregnant rabbits produced mainly 1 alpha 25-(OH)2D3, while those from nonpregnant animals produced 24,25-(OH)2D3 primarily. Plasma concentrations of calcium and phosphorus were significantly higher in fetuses than in mothers. Plasma levels of 250HD3 and 24,25-(OH)2D3 in fetuses were almost identical to those in mothers, whereas 1 alpha,25-(OH)2D3 levels in plasma were significantly higher in mothers than in their fetuses. A daily administration of 650 nmol vitamin D3 for 3 days to term pregnant rabbits caused a significant increase in calcium, phosphorus, 25OHD3, and 24,25-(OH)2D3 in maternal plasma, and in 25OHD3 and 24,25-(OH)2D3, but not calcium and phosphorus in fetal plasma. Treatment with large amounts of vitamin D3 also induced a marked suppression of 1 alpha-hydroxylase activity and a concomitant increase of 24-hydroxylase activity in the maternal but not in the fetal kidney. Plasma concentrations of 1 alpha,25-(OH)2D3 were not affected by treatment with large amounts of vitamin D3 in either the fetuses or the mothers. These results clearly indicate that the renal 25OHD3 metabolism in the fetus is regulated independently of that in the mother.

24,25-Dihydroxyvitamin D 3↗

Stage-synchronization of the seminiferous tubules after vitamin A replacement in vitamin A deficient golden hamsters.

The effect of vitamin A deficiency and vitamin A replacement on spermatogenesis in golden hamsters was studied using a light microscope. Male golden hamsters were fed a vitamin A deficient (VAD) diet from 3 weeks of age. Hamsters with a VAD diet reached maximum body weight at about 13 weeks. After 17 weeks, the body weight of the hamsters began to decrease. When their body weight decreased to 70 g, only Sertoli cells, spermatogonia, and a few spermatocytes were present within the seminiferous tubules. Administering retinol acetate (vitamin A) combined with a conventional diet to the VAD hamsters induced a reinitiation of spermatogenesis with stage-synchronization. At 9, 10, and 11 weeks after vitamin A replacement, the testes with active spermatogenesis possessed only a few successive stages of the seminiferous epithelial cycle.

Animals↗

Concentrations of vitamin A, beta-carotene and vitamin E in individual bovine follicles of different quality.

The degree of atresia of the follicle had no influence on the intrafollicular concentrations of beta-carotene, vitamin E and cholesterol. This might result from the passive transfer of these substances from blood to follicular fluid bound to high density lipoproteins. However, concentrations of vitamin A in follicular fluid were significantly (P less than 0.001) influenced by follicle quality, with highest concentrations (0.32 microgram/ml) in non-atretic follicles and lowest values (0.15 microgram/ml) in greatly atretic follicles. The higher concentrations of vitamin A in healthy follicles might be due to a local conversion of beta-carotene into vitamin A in follicular structures. By influencing hormone and protein synthesis, vitamin A may have a potential for local modulation of follicular development and therefore be one of the factors controlling recruitment, selection and growth of the dominant follicle in cattle.

Animals↗

Gas-liquid chromatographic determination of vitamin D in multivitamin preparations containing excess amounts of vitamin E.

Gas-liquid chromatographic (GLC) determination of vitamin D in multivitamin preparations containing excess amounts of vitamin E (a more than 2,500 weight ratio of dl-alpha-tocopheryl acetate to vitamin D) was investigated and a simplified routine method was established because the method reported previously (1) could not be applied to such special preparations. After applying the unsaponifiable matters of a sample to a phosphate-treated alumina column chromatography prepared according to MULDER et. al. (2), the eluate was evaporated and the residue was subjected to thin-layer chromatography (TLC) and GLC. When this method was applied to model preparations made by mixing vitamin D2 and dl-alpha-tocopheryl acetate (excess amounts), good results were obtained. Since the results on a commercial multivitamin preparation containing excess amounts of vitamin E were also satisfactory, it was confirmed that the proposed method could be used for simplified routine determinations.

Chromatography, Gas↗

Vitamin E or vitamin A protects chickens against E. coli infection.

The supplementation of either vitamin E (300 mg./kg. diet) or vitamin A (60,000 I.U./kg. diet) to a standard chick ration increased the protection of six week old immunized chickens against E coli infection, decreasing mortality from about 40% to 5%. The combination of the two vitamins, however, did not give as much protection as either vitamin alone. Vitamin E or A did not protect chicks from weight loss and severe morbidity due to infection, but slightly increased the rate of recovery.

Animals↗

The influence of (R)- and (S)-warfarin, vitamin K and vitamin K epoxide upon warfarin anticoagulation.

The contribution of (R)- and (S)-warfarin enantiomers, vitamin K and vitamin K epoxide and patient factors to inter-individual variability in daily warfarin requirements were examined in a group of 73 patients. Simple correlation analysis showed a significant positive relationship between INR values and plasma (S)-warfarin concentrations (r = 0.25; p = 0.038). Multivariate analysis for relationships with INR demonstrated a highly significant positive relationship between INR and (S)-warfarin (p = 0.004) and plasma vitamin K epoxide concentrations (p = 0.028), and a significant negative relationship between INR and plasma vitamin K concentrations (p = 0.034). Twenty five percent of variation in INR could be explained by these variables (adjusted R2 = 0.25). Correlation analysis of data showed that warfarin dosage was significantly and negatively correlated with patient age (r = -0.42; p <0.0001). Patient age accounted for 25% of variation in warfarin dosage requirements (R2 = 0.25). The combined effects of age and vitamin K appear to account for much of the inter-individual variability in warfarin dosage requirements.

Adult↗

Folate, vitamin B12 and vitamin B6 and one carbon metabolism.

The vitamins folic acid, B12 and B6 and B2 are the source of coenzymes which participate in one carbon metabolism. In this metabolism, a carbon unit from serine or glycine is transferred to tetrahydrofolate (THF) to form methylene-THF. This is either used as such for the synthesis of thymidine, which is incorporated into DNA, oxidized to formyl-THF which is used for the synthesis of purines, which are building blocks of RNA and DNA, or it is reduced to methyl-THF which used to methylate homocysteine to form methionine, a reaction which is catalyzed by a B12-containing methyltransferase. Much of the methionine which is formed is converted to S-adenosylmethionine (SAM), a universal donor of methyl groups, including DNA, RNA, hormones, neurotransmitters, membrane lipids, proteins and others. Because of these functions, interest in recent years has been growing particularly in the area of aging and the possibility that certain diseases that afflict the aging population, loss of cognitive function, Alzheimer's disease, cardiovascular disease, cancer and others, may be in part explained by inadequate intake or inadequate status of these vitamins. Homocysteine, a product of methionine metabolism as well as a precursor of methionine synthesis, was shown recently to be a risk factor for cardiovascular disease, stroke and thrombosis when its concentration in plasma is slightly elevated. There are now data which show association between elevated plasma homocysteine levels and loss of neurocognitive function and Alzheimer's disease. These associations could be due to a neurotoxic effect of homocysteine or to decreased availability of SAM which results in hypomethylation in the brain tissue. Hypomethylation is also thought to exacerbate depressive tendency in people, and for (colorectal) cancer DNA hypomethylation is thought to be the link between the observed relationship between inadequate folate status and cancer. There are many factors that contribute to the fact that the status of these vitamins in the elderly is inadequate. These factors are in part physiological such as the achlorhydria which affects vitamin B12 absorption and in part socioeconomic and habitual. We need more studies to confirm that these vitamins have important functions in the etiology of these diseases. We also need to establish if these diseases can be prevented or diminished by proper nutrition starting at a younger age.

Aged↗

Vitamin A, vitamin E and carotenoid status and metabolism during ageing: functional and nutritional consequences (VITAGE PROJECT).

Among the nutritional factors contributing to maintain health during ageing, fat-soluble vitamins (FSV) are crucial to protect against free radical-generated degenerative processes or impaired efficiency of the immune system. However, no sound scientific evidence is able to confirm specific dietary needs in vitamin A, vitamin E and carotenoids for the healthy elderly. VITAGE project aims at providing such evidence by undertaking studies on male volunteers from 3 European countries, aged between 20-75 years. Biomarkers and variables related to status, metabolism and functions will be measured either in steady-state conditions, or during dietary depletion and repletion in FSV. Original, yet already developed, methodologies will provide clear information about the physiological characteristics of vitamin A, vitamin E and carotenoids. Simultaneously, marketing opportunities for FSV-enriched dietetic foods, specifically designed for the elderly will be determined. The scientific and economical evidence obtained in this project will provide the basis to implement a EU nutritional policy towards the elderly and to develop a new sector of dietetic food products.

Adult↗

[Bioavailability and expression method of vitamin A, folate and vitamin E in foods].

It showed that the bioavailability and the expression of vitamin A, folate and vitamin E are very important to the analysis methods, the nutrition labeling, the food composition database and the determination of DRIs. Therefore, the bioabsorption, the bioavailability, the bioconversion, the bioefficacy and the expression of three important vitamins in foods namely vitamin A, folate and vitamin E was reviewed and summarized in this paper.

Absorption↗

The effect of recombinant human intrinsic factor on the uptake of vitamin B12 in patients with evident vitamin B12 deficiency.

We report on the use of recombinant human intrinsic factor (rhIF) in a new vitamin B12 absorption test. Holotranscobalamin (holoTC) was measured before and 24 hours after intake of three 9-mg doses of vitamin B12 (B12) and again 24 hours after intake of the same dose of B12 together with rhIF (rhIF-B12). Nine patients with evident vitamin B12 deficiency had a significantly higher increase in holoTC after intake of rhIF-B12 than after intake of B12. Twenty-eight patients with suspected vitamin B12 deficiency showed no additional increase in holoTC after intake of rhIF-B12. We conclude that rhIF promotes B12 absorption among patients with evident vitamin B12 deficiency.

Biological Transport↗

[Active vitamin D and vitamin K as therapeutic agents for osteoporosis].

Active vitamin D has been most widely used in Japan for the treatment of osteoporosis. However, clinical evidence for its efficacy as an anti-osteoporotic drug is scarce in terms of fracture prevention. Recent reports suggest that active vitamin D may prevent fracture not only through enhancement of intestinal calcium absorption but also by improving bone quality and/or strength independently of bone mass and by improving neuromuscular function to reduce the number of fall. Low serum concentrations of vitamin K have been reported in patients with osteoporosis, and serum osteocalcin appears to be undercarboxylated in these individuals, a process dependent on vitamin K. Undercarboxylated osteocalcin is also a significant risk for hip fracture. Clinical studies in Japan suggest that menatetrenone (vitamin K2) reduces skeletal losses and, in a small randomized clinical trial, it reduced the rate of vertebral fractures. Menatetrenone is currently used in Japan, the Republic of Korea and Thailand.

Humans↗

["Vitamin resistant" osteomalacia due to a defect in hepatic hydroxylation of vitamin D; reversible secondary-pseudo-hypoparathyroidism due to calcium administration].

The authors report a case of vitamin resistant osteomalacia in an adult due to an apparently acquired absence of hepatic hydroxylation of vitamin D. This case was also of interest as the osteomalacia caused a state of type II pseudo-hypoparathyroidism which proved reversible on calcium drip. Thus a defect of hepatic hydroxylation of vitamin D may be a cause of vitamin resistant osteomalacia in the adult apart from the forms already described related to defect of renal hydroxylation of vitamin D. Hypocalcemia may be responsible for hypoparathyroidism due to the coexistence of a rise of circulating immuno-reactive PTH and an increase in urinary cyclic AMP. Normalisation of the calcemia permitted in this case, restoral of the efficacy of endogenous PTH.

Calcium↗

Vitamin A intake and vitamin A deficiency in rural children.

The prevalence of vitamin A deficiency was estimated in 366 rural children in the age group of 1 to 15 years. In a systematically selected subsample of 90 children, the dietary intake of vitamin A was assessed. The prevalence of vitamin A deficiency signs ranged from 24.1 to 34.8%. The adequacy of dietary intake of vitamin A ranged from 8 to 12% when compared with the recommended dietary allowance. The dietary intake of children with and without vitamin A deficiency was not different (p greater than 0.05). The main source of beta carotene in the diet was cereals accounting for 47.9% of the total beta carotene intake.

Adolescent↗

[The effect of polychlorinated biphenyls on the vitamin A, vitamin E, and ascorbic acid status in young pigs].

Admixture for 14 to 26 days of concentrations between 1 mg/kg to 250 mg/kg of polychlorinated biphenyls, Delor 103, 105, and 106 (Chemko, Strázeke) to ready-mixed feedstuffs was studied in 5 experiments for its effects on 71 piglets and store pigs. Neither growth nor general health were in any way impaired. Polychlorinated biphenyls produced different effects upon vitamin A, vitamin E, and ascorbic acid levels in different organs. Vitamin A concentrations in blood serum, for example were reduced by 100 mg/kg and 250 mg/kg of Delor 105 as well as by 250 mg/kg of Delor 103. Liver levels were not significantly depressed. No changes were recordable from vitamin E levels in blood serum and liver. Ascorbic acid saturation of the organism was positively affected. Its concentrations and overall levels in the liver in all experimental groups were higher than those in all controls. Significant rise of ascorbic acid concentrations in blood serum, urine, and kidneys occurred merely in response to 100 mg/kg and 250 mg/kg of Delor 105 as well as to 250 mg/kg of Delor 103. No adverse effect of tissue-borne residues of polychlorinated biphenyls on the status of administered vitamins was recordable 1 to 4 months after termination of experimental supply. Feed intake with 1 mg/kg of Delor 105, which was equivalent to increased natural contamination, did not cause any negative phenomena in any of the probands.

Animals↗

Serum 25-OHD, vitamin A and vitamin E concentrations in healthy Finnish and Floridian women.

The concentrations of 25-hydroxyvitamin D (25-OHD), vitamin A and vitamin E were measured in serum samples of Finnish and Floridian women; the samples were collected in spring. The Floridians had twice as much 25-OHD in serum as the Finns, but the levels of the two other fat-soluble vitamins were equal. Thus, in Florida there is very little risk for vitamin D deficiency, and vitamin A and E status seems to be unaffected by differences in dietary habits.

Calcifediol↗

Serum selenium, vitamin A, vitamin E and cholesterol concentrations in Finnish and Japanese postmenopausal women.

Serum concentrations of vitamins A and E, selenium, and cholesterol were measured in 30 Finnish and 30 Japanese postmenopausal women. While both groups had identical serum vitamin A levels, the other serum factors differed significantly between the groups, the Finns having higher serum vitamin E and cholesterol and lower serum selenium levels. Adjusted to serum cholesterol, which correlated significantly with vitamin E in both groups, the vitamin E levels were, however, similar in the groups. The differences in the serum levels of these nutritional factors may be associated with the differences in the risk of coronary heart disease and cancer between Finnish and Japanese populations.

Cholesterol↗

Effect of long-term diet enrichment with selenium, vitamin E and vitamin B15 on the degree of fatty infiltration of the liver.

In a two-year experiment on 190 Wistar rats the effects were studied of the aging process and diet enrichment with selenium, vitamin E and vitamin B15 (pangamic acid) on the degree of fatty infiltration of the liver determined histochemically with Oil Red O. The degree of fatty infiltration of the liver was assessed by the method of quantitative analysis using a computer image analyser Quantimet 720. System 30 (Cambridge Instruments). The process of aging of the animals was associated with increasing fatty infiltration of the liver. Selenium had a two-phase effect on the degree of fatty infiltration: in the first 12 months of selenium administration (0.1 ppm of sodium selenite per 100 g of the diet) fatty infiltration of the liver was decreasing, and after 18 months of the experiment this effect disappeared and the degree of fatty infiltration was not different from that in the control group. Contrary to this, vitamin E administration 6 mg/100 g of the diet increased the degree of fatty infiltration during the first 12 months. After 18 months a reverse effect appeared with inhibition of the progression of fatty infiltration. Thus the two-phase effect of vitamin E was a reverse of selenium effect. Addition of vitamin B15 to the diet (2.5 mg/100 g of diet) increased the degree of fatty infiltration of the liver which was maintained at a stable level throughout the whole experiment, i.e. 12-18 months.

Animals↗