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Tissue levels of S-adenosylmethionine and S-adenosylhomocysteine in rats fed methyl-deficient, amino acid-defined diets for one to five weeks.

The levels of S-adenosylmethionine (AdoMet) and of S-adenosylhomocysteine (AdoHcy) as well as the ratio of AdoMet/AdoHcy were determined in the liver, lungs, testes and kidneys of weanling male rats fed a commercial chow diet or 5 different amino acid-defined diets for 1-5 weeks. The amino acid-defined diets used were as follows: diet 1, supplemented with methionine, choline, folic acid and vitamin B12; diet 2, deficient in methionine and choline; diet 3, deficient in methionine alone; diet 4, deficient in choline alone; diet 5, deficient in methionine, choline, folic acid and vitamin B12. All methionine-deficient diets were supplemented with an equimolar dose of its metabolic precursor, homocystine. The animals were sacrificed after 1, 3 and 5 weeks of treatment. In animals fed either the chow diet or diet 1, liver was the organ found to contain the highest levels of AdoMet and AdoHcy. Similarly, in animals fed diet 1 or chow, the testes and lungs contained the lowest level of AdoMet, while the lungs contained the lowest levels of AdoHcy. In general, the tissue levels of AdoHcy and AdoMet in rats fed diet 1 were very similar to the corresponding values found in chow-fed rats. Diet 1 feeding, however, led to higher hepatic levels of AdoMet than did the administration of the chow diet. The administration of the methyl-deficient diets generally led to decreased hepatic AdoMet contents at 3 and 5 weeks; the methyl-deficient diets also led to increased AdoHcy contents and decreased AdoMet:AdoHcy ratios when compared with diet 1. Linear regression analysis showed a significant direct correlation between the observed hepatic AdoMet levels and the methyl content of the diet as well as an inverse correlation between hepatic AdoHcy levels and dietary methyl contents. Unlike liver, the lung and testes did not show any decrease in AdoMet content following feeding of the methyl-deficient diets. These tissues did show, however, early significant increases in AdoHcy contents and corresponding decreases in the ratios of AdoMet:AdoHcy. These changes were found to be proportional to the dietary methyl content. The renal contents of AdoMet, AdoHcy and the ratio of AdoMet/AdoHcy were unaffected by any of the diets administered except for diet 5. The administration of diet 5 to rats for 5 weeks led to a significant increase in renal AdoHcy. These results provide evidence indicating that dietary methyl insufficiency may exert its role in carcinogenesis through a decreased availability of AdoMet in vivo.

Animals↗

[A correlation study on homocysteine metabolism in pregnant women and neural tube defects in urban and rural areas].

Serum levels of homocysteine, folic acid and vitamin B12 in pregnant women in urban and rural areas were compared to study the relationship between homocysteine metabolism and neural tube defects. Four hundred and eleven serum specimens were sampled randomly from a serum bank for women with early pregnancy in Beijing area, 195 from urban and 216 from rural. Their levels of homocysteine were determined by high performance liquid chromatography combined with electrochemical methods, and those of folic acid and vitamin B12 by radioimmunoassay. Results showed that level of homocysteine was significantly higher in rural pregnant women than that in urban, with 9.31 mumol/L and 5.73 mumol/L, respectively, level of vitamin B12 was lower in rural than that in urban women, with 210.09 pmol/L and 233.35 pmol/L, respectively, and level of folic acid was higher in rural than that in urban women, but no significant difference in deficiency of folic acid between rural and urban was found. The average ratio of folic acid to homocysteine and that of vitamin B12 to homocysteine were higher in rural than those in urban women. It suggests that abnormal metabolism of homocysteine usually correlates with high incidence of neural tube defects in rural area.

Adult↗

Evaluation of oral administration of folic and folinic acid to prevent folate deficiency in patients with inflammatory bowel disease treated with salicylazosulfapyridine.

In order to evaluate the efficacy of oral administration of a pharmacological dose of folic or of folinic acid to prevent the folate deficiency in patients with inflammatory bowel disease (IBD) treated with salicylazosulfapyridine (SASP) (1g twice daily at meal times), two groups of 15 patients with IBD received 15 mg/day of folic or folinic acid for one month. In both the groups there were ten patients affected by Crohn's disease and five patients affected by ulcerative colitis. Before starting the treatment, the plasma folate and the red blood cell (RBC) folate concentrations did not statistically differ between the two groups. After one month the mean increase in RBC folate concentration was significantly greater after folinic therapy then after folic acid therapy (910 +/- 383 versus 570 +/- 212 ng/ml; p less than 0.01), while no difference was observed in the mean increase of plasma folate level (19.8 +/- 6.6 versus 18.5 +/- 5.0 ng/ml). It was concluded that: a) both folic and folinic acid could restore and enlarge the body stores of folate in patients with IBD treated with SASP, when administered at the dose of 15 mg daily for one month; b) folinic acid seems to be more efficient in enlarging the body stores of the vitamin than folic acid.

Administration, Oral↗

Folate supplementation during methotrexate treatment of patients with rheumatoid arthritis. An update and proposals for guidelines.

The efficacy of weekly low-dose methotrexate treatment of rheumatoid arthritis is well documented. Efficacy and adverse effects are both dose dependent. and adverse effects rather than lack of efficacy are the main reason for discontinuing therapy. Several adverse effects are related to folate deficiencies, largely due to the antifolate properties of methotrexate. In order to reduce adverse effects without compromising drug efficacy, numerous clinical investigations have been performed using supplementation with folic or folinic acid during methotrexate therapy of patients with rheumatoid arthritis, addressing both the timing of folate supplementation and the weekly folate-to-methotrexate ratio. Based on these studies, an individually adjusted supply of folic acid rather than folinic acid is proposed. For many patients, however, a properly balanced diet is sufficient to avoid folate deficiency.

Antirheumatic Agents↗

Cognitive effects of nutritional deficiency.

Deficiencies of various nutrients, primarily vitamins, impair cognition. The link is strongest for vitamin B12, thiamine, and niacin. Yet even for these, the role of mild "subclinical" or multiple deficiencies in the genesis of mental dysfunction is unclear. Most information in this field is based on animal studies often poorly applicable to the human condition or on clinical pathology complicated by advanced age, alcoholism, and intercurrent disease. There is a need for well controlled, double-blind, prospective trials to elucidate the cognitive effects of malnutrition.

Adult↗

Vitamin metabolism and therapy in ophthalmology.

Vitamin deficiency states are important in the genesis of many ocular disorders. Deficiencies may be due to poor dietary intake, or to alterations in metabolism produced by some commonly prescribed medications or by certain diseases. Furthermore, some vitamins may exert important pharmacologic effects on the normal eye. The ocular effects of deficiencies and excesses of specific vitamins, and the therapeutic uses of each vitamin, are reviewed.

Animals↗

The use of folates concomitantly with low-dose pulse methotrexate.

Toxicities related to low-dose weekly methotrexate are largely due to its antifolate properties. Preexisting folate deficiency is associated with methotrexate toxicity in some patients. At the onset of methotrexate therapy and throughout therapy, the physician should be vigilant regarding one or more nutrient deficiencies. A multivitamin and, where appropriate, specific daily folic acid supplements should be employed. The only regimen known presently (through controlled trials) to treat side effects is the low-dose folinic acid (leucovorin) protocol outlined herein. Folic acid may be helpful to treat mild gastrointestinal symptoms. Folinic acid supplementation should be considered prophylactically in those requiring methotrexate who are at increased risk of hepatic disease. Other possible factors besides methotrexate should always be considered with the onset of new patient complaints or laboratory abnormalities. Claims that folic acid therapy is safer and more convenient than folinic acid seem unwarranted when one reviews the literature carefully. Cost differences between folic acid supplementation and folinic acid supplementation have been exaggerated.

Antidotes↗

A national survey of iron and folate status in pregnant women in Switzerland.

Women often do not meet the increased iron and folate needs of pregnancy. Maternal iron-deficiency anemia is associated with poor maternal and infant outcomes, including preterm delivery and low birth weight. Poor folate status increases risk for maternal anemia, spontaneous abortion, and congenital defects. Because of this, supplemental iron and folate are often recommended during pregnancy. There are few data on iron and folate status in pregnant women in Switzerland. We measured iron and folate status in a national sample of Swiss pregnant women, estimated the prevalence of anemia, and determined if supplement use is associated with iron and/or folate status in this group. A 3-stage probability to size cluster sampling method was used to obtain a representative national sample of pregnant women (n = 381) in the second and third trimester. We measured hemoglobin, hematocrit, mean corpuscular volume, and serum folate and ferritin concentrations. Serum transferrin receptor concentration was determined in anemic subjects. The use of iron and folate supplements was evaluated by questionnaire. Mean hemoglobin (+/- SD) in the sample was 123 g/L (+/- 1.0). The prevalence of anemia was 6%. Of the 21 anemic women, 11 were iron-deficient, giving an iron-deficiency anemia prevalence of 3%. Nineteen percent of women had low serum ferritin concentrations (< 12 micrograms/L) and 4% had low serum folate concentration (< 2.5 micrograms/L). Supplements containing iron were taken by 65% of women, and 63% were taking folate-containing supplements. Women in the second and third trimester taking folate-containing supplements had significantly higher serum folate concentrations compared to those not taking a folate supplement (p < 0.001). In the third trimester, women taking iron-containing supplements had significantly higher serum ferritin concentrations compared to those not taking an iron-containing supplement (p < 0.01). Our findings indicate that iron and folate status appears to be adequate in the majority of pregnant women in Switzerland, and that use of iron and folate supplements may have a positive impact on status.

Adolescent↗

Epidemiology of anemia in the elderly: information on diagnostic evaluation.

A rise in the aging population has been predicted, and, as a result, it is expected that the incidence of age-related health conditions will also increase. Although common in the elderly, anemia is often mild and asymptomatic and rarely requires hospitalization. However, untreated anemia can be detrimental, because it is associated with increased mortality, poor health, fatigue, and functional dependence and can lead to cardiovascular and neurological complications. Several factors have been suggested to cause anemia in this population, for example, blood loss or chronic disease. In some cases, the cause is unknown. It has been suggested that this is a result of the presence of comorbid conditions that can mask the symptoms of anemia. Therefore, appropriate diagnosis and management strategies of anemia in the elderly need to be identified, particularly because anemia may indicate the presence of other serious diseases.

Aged↗

Rescue of embryonic lethality in reduced folate carrier-deficient mice by maternal folic acid supplementation reveals early neonatal failure of hematopoietic organs.

The reduced folate carrier (RFC1) is an important route by which the major blood folate, 5-methyltetrahydrofolate, is transported into mammalian cells. In this study we determined the consequences of inactivation of RFC1 in mice by homologous recombination. While RFC1-null embryos died in utero before embryonic day 9.5 (E9.5), near-normal development could be sustained in RFC1(-)/- embryos examined at E18.5 by supplementation of pregnant RFC1(+/-) dams with 1-mg daily subcutaneous doses of folic acid. About 10% of these animals went on to live birth but died within 12 days. These RFC1(-)/- mice showed a marked absence of erythropoiesis in bone marrow, spleen, and liver along with lymphoid depletion in the splenic white pulp and thymus. In addition, there was some impairment of renal and seminiferous tubule development. These data indicate that in the absence of RFC1 function, neonatal animals die due to failure of hematopoietic organs.

Alleles↗

Nutritional anemia in the English-speaking Caribbean and Suriname.

Anemia is a problem in all countries of the English-speaking Caribbean where data are available. It affects mostly preschool age children and pregnant and lactating women. The most common cause is a deficiency of iron. This is probably due to an adequate intake with a low absorption. A deficiency of folate is also probably a responsible factor in the pathogenesis of some of the anemias. Anemias associated with parasitic infestations such as hookworm and whipworm and hemoglobinopathies such as sickle cell anemia are also noted.

Adolescent↗

Studies of methionine cycle intermediates (SAM, SAH), DNA methylation and the impact of folate deficiency on tumor numbers in Min mice.

Several epidemiological studies have suggested a modulatory effect of dietary folate intake on the risk of colorectal cancer. The molecular basis for this inverse association is not clearly understood, but may involve alterations in DNA methylation. In this study, we examined the levels of methylation intermediates [S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH)] and of global DNA methylation in the pre-neoplastic small intestine of Min (multiple intestinal neoplasia) mice. We also studied the effect of folate/choline deficiency on these parameters and on tumor multiplicity in this animal model. In folate-adequate Min mice, we identified positive linear correlations between SAM or SAH and tumor numbers (R(2) = 0.38, P < 0.005; R(2) = 0.26, P = 0.025, respectively). A positive correlation between global DNA hypomethylation and tumor multiplicity was also observed (R(2) = 0.29, P = 0.014). These three biochemical determinants (SAM, SAH and DNA hypomethylation) may, therefore, serve as early markers of cell transformation. Folate/choline deficiency, however, did not produce a consistent effect on tumor numbers in three separate experiments. As an increase in tumor numbers was observed only in folate- and choline-deficient mice with low levels of SAM and DNA hypomethylation, the modulatory role of folate may be dependent on the transformation state of the cell.

Animals↗