Impaired methionine synthesis and DNA hypomethylation may be involved in VPA-induced teratogenesis.

There is new evidence that a good folate status may play a critical role in the prevention of neural-tube defects and in lowering elevated homocysteine concentrations. This adequate folate status may be achieved through folic acid dietary supplementation. Folate is a water-soluble vitamin with a low potential toxicity. However, the possible consequences of long-term high-dose folic acid supplementation are unknown, especially those related to the methionine cycle, where folate participates as a substrate. With the aim of evaluating such possible effects, four groups of Wistar rats were classified on the basis of physiological status (virgin v. pregnant) and the experimental diet administered (folic-acid-supplemented, 40 mg/kg diet v. control, 2 mg folic acid/kg diet). Animals were fed on the diets for 3 weeks. Results showed that gestation outcome was adequate in both groups regardless of the dietary supplementation. However, there were reductions (P < 0·001) in body weight and vertex-coccyx length in fetuses from supplemented dams v. control animals. Folic acid administration also induced a higher (P < 0·01) S-adenosylmethionine : S-adenosylhomocysteine value due to increased S-adenosylmethionine synthesis (P < 0·01). However, hepatic DNA methylation and serum methionine concentrations remained unchanged. Serum homocysteine levels were reduced in supplemented dams (P < 0·05). Finally, pregnancy caused lower serum folate, vitamin B6 and vitamin B12 levels (P < 0·05). Folic acid administration prevented the effect of pregnancy and raised folate levels in dams, but did not change levels of vitamins B12 and B6. These new findings are discussed on the basis of potential benefits and risks of dietary folic acid supplementation.

Patients who follow a gluten-free diet (GFD) may be prone to nutritional deficiencies, due to food restriction and consumption of gluten-free products. The aim was to assess nutritional status in celiac children and adolescents on a long-term GFD. A cross-sectional age and gender-matched study in 70 celiac and 67 non-celiac volunteers was conducted, using dietary, anthropometric, biochemical parameters, and assessing bone mineral density and physical activity. Adequacy of vitamin D intake to recommendations was very low, in both groups, and intakes for calcium and magnesium were significantly lower in celiac volunteers. Celiac children and adolescents may have a higher risk of iron and folate deficiencies. Both groups followed a high-lipid, high-protein, low fiber diet. Median vitamin D plasma levels fell below reference values, in celiac and non-celiac participants, and were significantly lower in celiac girls. Other biochemical parameters were within normal ranges. Anthropometry and bone mineral density were similar within groups. With the exception of some slightly lower intakes, children and adolescents following a GFD appear to follow the same trends as healthy individuals on a normal diet. No effect of food restriction or gluten-free product consumption was observed.

Carbon tetrachloride (CCl,) administration to rats produces hepatic cirrhosis and supplementation with Sadenosylmethionine (SAM) can partially prevent CCLinduced liver injury. These effects are thought to be caused by oxidative stress and the subsequent formation of free radicals, but the mechanism whereby this occurs and the accurate nature of the mechanisms by which SAM exerts its protective action are not well understood.The effect of short-term administration of CCl, on hepatic DNA methylation and on S A M and S-adenosylhomocysteine (SAH) were assessed. CCl, administration to rats for 3 weeks resulted in hypomethylation of liver DNA, determined by comparing the extent to which DNA from livers of control or treated animals could be methylated in uitro using [3H-methyl] Carbon tetrachloride (Cch), a toxic agent commonly used for the study of liver diseases in different experimental animal models, is a substrate for P-450 where it is converted to CC1, radicals, which generate CC1300 radicals by reacting with molecular oxygen. Because CC1, radicals react with membranes and induce lipid peroxidation, membrane damage by free radical chain reaction has been proposed as the major cause of hepatocellular injury by CC14, the probable initial event being mitochondria1 membrane injury. ' We have previously shown that administration of CCl, to rats for 3 weeks produces liver steatosis.' When CC14 administration was maintained for 6 additional weeks, the majority of the animals had developed cirrhosis. The later histological alterations were accompanied by a decrease of hepatic S-adenosylmethionine (SAM) synthetase activity and glutathione (GSH) depletion. ' The above results were partially corrected by the administration of exogenous SAM, but the mechanism whereby this occurs and the accurate nature of the mechanisms by which SAM exerts its protective action are not well understood. SAM serves as the donor of methyl groups in many transmethylation reactions (e.g., DNA-, phospholipid-, and protein-methylation).In donating its methyl group, SAM is converted to Sadenosylhomocysteine (SAH), which in turn is hydrolyzed to homocysteine and adenosine. Homocysteine can then be remethylated to methionine (via Blz-dependent methionine synthase or additionally in liver by betaine homocysteine methyltransferase) or degraded via the transsulphuration pathway. The transsulphuration pathway is the principal mechanism by 1310

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There is new evidence that good folate status may play a critical role in the prevention of neural tube defects and in the maintenance of adequate homocysteine levels, an amino acid recently identified as a risk factor for cardiovascular disease. This has led to different folate recommendations, all of them much higher than the present dietary recommendations. Folic acid is a water-soluble vitamin with a low potential toxicity. However, the possible consequences of long-term, high folate intakes are unknown. Therefore, the present study was undertaken to determine the effects of long-term, high dietary folate supplementation on gestational and nutritional markers in pregnant and virgin rats. Four groups of Wistar rats were classified on the basis of physiological status (virgin or pregnant) and the experimental diets administered (folic acid supplemented, 40 mg/kg diet; or control diet, 2 mg folic acid/kg diet). Rats were fed their respective diets for 3 wk. Two critical periods were used for metabolic balance studies (experimental d 1-5 and 17-21), which involved the determination of fat and protein digestibilities as well as metabolic protein utilization (MPU) and net protein utilization (NPU). Gestational development (number of live fetuses) was adequate in both diet groups regardless of folate supplementation. However, body weight and vertex-coccyx length in fetuses from supplemented dams were less than (P < 0.0001) in fetuses of control dams. Fat and nitrogen digestibilities were not affected by supplementation, but MPU and NPU coefficients were significantly lower (P < 0.05) in the folic acid-supplemented groups, irrespective of physiological status, compared to control rats. These new findings of macro-micronutrient interactions caused by high folate supplementation are discussed on the basis that the vitamin may act as a xenobiotic more than as a nutrient.

Historically, food fortification has served as a tool to address population-wide nutrient deficiencies such as rickets by vitamin D fortified milk. This article discusses the different policy strategies to be used today. Mandatory or voluntary fortification and fortified foods, which the consumer needs, also have to comply with nutritional, regulatory, food safety and technical issues. The ‘worldwide map of vitamin fortification’ is analysed, including differences between develop and developing countries. The vitamins, folate and vitamin D, are taken as practical examples in the review of the beneficial effect of different strategies on public health. The importance of the risk–benefit aspect, as well as how to identify the risk groups, and the food vehicles for fortification is discussed.

Valproate (VPA) is a drug widely used to treat epilepsy, but it has serious adverse effects including hepatotoxicity, teratogenicity and antifolate activity. The mechanism underlying VPA toxicity is unclear although an interaction with folate and other metabolites involved in methionine metabolism has been suggested. The present study was undertaken to evaluate potential changes in the metabolic function of the methionine cycle after acute exposure to a single dose of valproate. Female Wistar rats (n = 30) were treated with 400 mg/kg of VPA. Different groups of six rats were killed at 1 (t1), 3 (t3), 6 (t6), 9 (t9), and 24 (t24) hours after the injection. One group of rats was untreated (n = 6) and was considered the control group. The most pronounced effects of VPA administration were observed 1 h after drug injection. VPA induced a 56% reduction in methionine adenosyltransferase activity and a 54% reduction in plasma vitamin B-6. Increases in the hepatic concentration of S-adenosylhomocysteine and oxidized glutathione, and a reduction in the S-adenosylmethionine/S-adenosylhomocysteine transmethylation ratio also occurred at 1 h. All of these alterations, however, were normalized within 24 h, parallel with a decrease in serum VPA concentration. The acute effects of VPA suggest that the alterations in the methionine cycle could be the common mechanism underlying the hepatotoxic, teratogenic and antifolate effects of the drug.