Biomedical subjects

E Alonso-Aperte

Publications and source records attributed to E Alonso-Aperte.

7 recordsLinked to original sources

PubMed2000

High-dose folic acid supplementation in rats: effects on gestation and the methionine cycle.

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.

Animals↗

PubMed2000

Drugs-nutrient interactions: a potential problem during adolescence.

The concept of drug-nutrient interactions is not new, but it has only recently gained currency in medicine. Although the elderly are normally considered to be at particular risk, other groups may also be at risk: infants, adolescents, pregnant women, alcohol and tobacco users, etc. In infants and adolescents there are several factors that may influence the possible interactions: firstly, nutrient needs are usually higher, mainly micronutrients; systems for detoxification of anutrients are not complete; the tendency to restricted diets (especially girls) that are unable to cover the actual recommended intakes for a number of micronutrients (i.e. vitamins); and the dangerous increase in alcohol consumption either in males or females. Administration of drugs in population with adequate vitamin intake is usually not a problem, but administration of drugs in those with borderline intake of vitamins or in patients with low nutritional status can result in symptomatic vitamin deficiency states. The groups at risk of poor vitamin status are smokers (a high proportion of adolescents are active smokers); dieters (skipping meals and dieting to lose weight frequently compromise micronutrient intake, and it should be considered that it is extremely difficult to meet all the requirements at intakes of less than 1,200 calories per day), oral contraceptive users, and pregnant and lactating women, excessive alcohol users, etc. The chapter also focuses on the case of folate: rapidly dividing tissues during the adolescent growth spurt increase requirements for folate. Because of this increased need, folate status appears to be of concern during the age of this rapid growth. A variety of drugs are known to interfere with vitamin utilization by blocking or altering transformation of the vitamin to its metabolically active form. Serum folate levels are known to be low in a high percentage of patients with rheumatoid arthritis, suggesting that aspirin alters the transport of folate by competition for binding sites on serum proteins. Methotrexate, a drug commonly used at low doses for the treatment of psoriasis, rheumatoid arthritis and certain liver disorders, limits the availability of methyl groups derived from one-carbon metabolism by inhibiting competitively a key enzyme in the intracellular folate metabolism. In humans, the antiepileptic drug valproic acid (VPA) is associated with two major adverse effects: teratogenicity and folate deficiency. The mechanisms by which VPA exerts the teratogenic or antifolate effect remain unclear, but an alteration in the methionine cycle is the strongest hypothesis proposed.

Adolescent↗

PubMed1999

Impaired methionine synthesis and hypomethylation in rats exposed to valproate during gestation.

BACKGROUND: The antiepileptic drug valproic acid (VPA) may be teratogenic. The mechanism of teratogenicity remains unclear, but it has been hypothesized that VPA interferes with folate metabolism. OBJECTIVE: To study the effect of VPA on the methionine cycle and transmethylation reactions in pregnant rats. METHODS: Wistar rats were treated with VPA (300 mg/kg/day) on gestation days 8, 9, and 10, alone or in combination with folinic acid (FOL, 4 mg/kg/day) on gestation days 8, 9, and 10 or S-adenosylmethionine (SAM, 10 mg/kg/day) throughout gestation days 1 to 10. RESULTS: VPA induced a reduction in maternal methionine serum concentration (p < 0.05) caused by a 24% reduction of methionine synthase activity in liver. This provoked hepatic DNA hypomethylation, although the methylation ratio (S-adenosylmethionine/S-adenosylhomocysteine) was not altered. Homocysteine, folate, and vitamin B12 serum concentrations, as well as methionine adenosyltransferase and betaine homocysteine methyltransferase hepatic activities, did not change. In fetuses exposed to VPA, no effect was observed in hepatic methionine content, but the methylation ratio was reduced (p < 0.01), leading again to hepatic DNA hypomethylation. Coadministration of FOL prevented VPA-induced alterations in methionine synthesis and corrected fetal DNA hypomethylation. By contrast, SAM did not exert a protective effect on fetal DNA methylation. CONCLUSION: Impaired methionine synthesis and DNA hypomethylation may be involved in VPA-induced teratogenesis.

Analysis of Variance↗

PubMed1999

High dietary folate supplementation affects gestational development and dietary protein utilization in rats.

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.

Animals↗

PubMed1996

Brain folates and DNA methylation in rats fed a choline deficient diet or treated with low doses of methotrexate.

In a recent study we have demonstrated that induced changes in several parameters of one-carbon metabolism in livers of rats fed either a choline deficient diet or treated with low doses of methotrexate may be reversed through restoration of an adequate choline diet and discontinuing of methotrexate (MTX) administration. The present study was aimed at comparing these two treatments for their effect on brain: total folate was 0.69 +/- 0.35 nmol/g in the control group and was significantly lower in the other two groups (0.25 +/- 0.06 in the MTX and 0.45 +/- 0.24 nmol/g in the choline deficient groups, p < 0.01). Both treatments were associated with elongations of the glutamate chains of the folate molecules: the proportion of hepta- and octaglutamyl folates increased from 16% to 31% in the MTX treated and to 33% in the choline deficient group, accompanied with concomitant decreases in the concentrations of tetra- and pentaglutamyl folates. MTX could not be detected in brain tissue in contrast to previous observations of significant amounts found in liver. DNA was significantly (p < 0.05) undermethylated in both treated groups compared to controls. Results are discussed on the basis of the possibility that choline deficiency and MTX treatment appear to impair the capacity of tissues, either a peripheral one as liver or a central one as brain, to incorporate folate.

Animals↗

PubMed1995

Carbon tetrachloride-induced hepatic injury is associated with global DNA hypomethylation and homocysteinemia: effect of S-adenosylmethionine treatment.

Carbon tetrachloride (CCl4) administration to rats produces hepatic cirrhosis and supplementation with S-adenosylmethionine (SAM) can partially prevent CCl4-induced 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 CCl4 on hepatic DNA methylation and on SAM and S-adenosylhomocysteine (SAH) were assessed. CCl4 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 vitro using [3H-methyl] SAM as methyl donor. This CCl4 effect on DNA methylation was corrected by the administration of SAM (10 mg/kg/d, intramuscularly), with values of methyl groups incorporation comparable with those observed in the control animals. hepatic SAM was decreased by CCl4 (65.3 +/- 5.27 vs. 102.2 +/- 4.89 nmol/g; P < .05) and SAH was increased (69.5 +/- 14.6 vs. 29.4 +/- 3.83 nmol/g; P < .05). This led to a marked reduction of the SAM/SAH ratio (the methylation ratio) from 3.47 in control rats to 0.94 in CCl4-treated animals (P < .05). SAM treatment partially prevented (P < .05) the reduction of the ratio SAM/SAH induced by CCl4. CCl4 also induced a marked elevation of serum homocysteine levels (more than 20-fold; P < .001), which was partially prevented by SAM administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

[Morphological changes induced by valproate and its administration concomitant with folinic acid or S-adenosylmethionine in pregnant rats].

Neural tube defects (NTD) are serious congenital abnormalities that have a multifactorial etiology, including both genetic and environmental effectors (for example, diet and/or drugs). Valproic acid (VPA) is a frequently used anti-epileptic drug that has a potentially teratogenic character, as well as the capacity for inducing NTD and other less serious malformations. However, the mechanism of action of VPA has not been clearly established, and it has been suggested that it interferes in the folate cycle and therefore, with the methionine/methylation, possibly through a metabolic blocking of some biomarker that is a key of the cycle, such as for example S-adenosylmethionine (SAM) and folic acid (FA). The objective of the present study is to analyze the morphological and histological changes, which can occur in a high risk experimental model after the administration of VPA as well as for the induction of NTD and other malformations. In addition, the protective roles of the administration of folic acid, 5-formyltetrahydrofolate (FOL) and S-adenosylmethionine (SAM) are assessed. For this pregnant "Wistar" rats classified according to the following treatments: 1) VPA (300 mg/kg/day on days 8, 9, and 10 of the pregnancy); II) VPA (300 mg/kg/day on days 8, 9, and 10 of the pregnancy) and FOL (4 mg/kg/day i.p. on days 8, 9, and 10 of the pregnancy); III) VPA (300 mg/kg/day on days 8, 9, and 10 of the pregnancy) + SAM (10 mg/kg/day, on days 1-10 of the pregnancy); IV) CONTROL (no treatment). VPA decreases the fertility index by 25% compared to the control group, it increases the number of reabsorptions by mother (1.3 +/- 0.5 vs 1.0 +/- 0.5), and decreases the number of fetuses compared to the control (9.0 +/- 1.4 vs. 12.6 +/- 0.9). In the VPA + FOL group, the numbers for these parameters approach those of the control group and the VPA + SAM group is no different from the VPA group, showing no protective factors. With respect to the bone alterations observed, when these are grouped according to whether they affect the skull, trunk, and extremities, it is seen that there are no significant differences between the groups. The histological study and the immunohistochemical analysis show liver alterations in all groups treated, and a lower number of lymphocytes in the VPA group, and a greater number of Kupffer cells, The results are discussed in relation to, first, the effect of VPA per se in the interference of the methionine/methylation cycle, and secondly, with regard to how folic acid and/or S-adenosylmethionine can improve or not some of the harmful effects induced by VPA.

Abnormalities, Drug-Induced↗