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

Alonso-Aperte, Elena; Úbeda, Natalia; Achón, María; Pérez-Miguelsanz, Juliana; Varela‐Moreiras, Gregorio

doi:10.1212/wnl.52.4.750

Cited by 76 publications

(41 citation statements)

References 35 publications

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“…VPA induced a reduction in methionine serum concentration (P`0.05) caused by a 24% reduction of methionine synthase activity. This provoked hepatic DNA hypomethylation, and both, impaired methionine synthesis and DNA hypomethylation may be involved in VPAinduced teratogenesis (Alonso- Aperte et al, 1999). In addition, we also observed that VPA alters normal gestation reducing the fertility index, and induces skeletal modi®ca-tions on the skull, appendicular bones, vertebrae and ribs (Ubeda et al, 1996).…”

Section: The Case Of Folatementioning

confidence: 60%

Drugs–nutrient interactions: a potential problem during adolescence

Alonso-Aperte

Varela‐Moreiras

2000

Eur J Clin Nutr

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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 in¯uence the possible interactions: ®rstly, nutrient needs are usually higher, mainly micronutrients; systems for detoxi®cation 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 micronutients (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 de®ciency 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 dif®cult to meet all the requirements at intakes of less than 1200 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 de®ciency. 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.

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Section: The Case Of Folatementioning

confidence: 60%

Drugs–nutrient interactions: a potential problem during adolescence

Alonso-Aperte

Varela‐Moreiras

2000

Eur J Clin Nutr

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“…Valproate alters folate metabolism in the embryo [66] and affects methionine synthase, therefore disrupts the methylation cycle, inducing DNA hypomethylation [67]. The folate deficiency is a well-known cause of neural-tube defects [17,26].…”

Section: Discussionmentioning

confidence: 99%

Critical Evaluation of Antiepileptic Drugs in Epileptic Pregnant Women - Hungarian Experiences

Czeizel¹,

Bánhidy²

2011

Open Drug Saf J

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Abstract:The prevalence of epilepsy is 0.3-0.6% in pregnant women and the higher rate of structural birth defects, i.e. congenital abnormalities (CAs) was recognized in their children. There are four aims of this review based on the population-based large data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA), 1980-1996 with the good validity of CA-diagnoses. (I) Most studies on the teratogenic/fetotoxic effects of antiepileptic drugs (AED) had too small samples therefore underpowered, thus the evaluation the findings of different studies together are appropriate to draw significant conclusions, therefore the data of HCCSCA are presented here. Of 22,843 cases with CA, 95 (0.42%), while of 38,151 controls without CA, 90 (0.24 %) had mothers with medically recorded epilepsy (OR with 95% CI: 1.8, 1.3-2.4) and AED in the prenatal maternity logbook. (II) Hungary had different spectrum of AED as in Western countries, thus the teratogenic potential of some less-known AED (e.g. sultiame) can be evaluated. (III) The efficacy of recent special medical care of epileptic pregnant women introduced in 1990 is worth checking. There was no significant increase in the proportion of monotherapy but the rate of total CAs decreased by 20% in the 1990s compared to the 1980s. (IV) Folic acid may reduce the teratogenic potential of some AED, nevertheless this analysis revealed that folic acid was used less frequently by epileptic pregnant women than by non-epileptic pregnant women. Thus an international consensus statement is an urgent task in this topic.

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“…In adults taking VPA, folate depletion is normally not observed (33), whereas in children receiving VPA, folate depletion may develop (18). Again, multiple mechanisms and interactions may play a role: in pregnant Wistar rats, VPA directly impairs the activity of methionine synthase, the enzyme that remethylates Hcy to methionine (34).…”

Section: Discussionmentioning

confidence: 99%

Hyperhomocysteinemia in Children Treated with Antiepileptic Drugs Is Normalized by Folic Acid Supplementation

Huemer

Ausserer

Graninger³

et al. 2005

Epilepsia

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Summary:Purpose: To assess the prevalence of hyperhomocysteinemia in pediatric patients treated with antiepileptic drugs (AEDs) and to evaluate the effect of folic acid supplementation on plasma total homocysteine (tHcy) concentrations in hyperhomocysteinemic patients.Methods: 123 patients from three regional hospitals participated in the study. Patients with hyperhomocysteinemia were included in a 3-month double-blind randomized trial testing oral folic acid supplementation (1 mg/day) versus placebo.Results: Hyperhomocysteinemia (tHcy >10.4 µmol/L) was present in 19 of 123 patients. Patients with hyperhomocysteinemia were older (13.7 ± 4 vs. 11.0 ± 3.9 years) and had significantly lower folate and cobalamin concentrations. Multidrug (two or more) AED treatment and duration of therapy correlated significantly with elevated total homocysteine (tHcy) and low folate. In contrast, polymorphisms in the methylene tetrahydrofolate reductase gene (MTHFR 677 C→T, 1298 A→C, 1793 G→A) had no significant impact on tHcy. Nine of 19 patients with hyperhomocysteinemia were randomized to placebo, whereas the remaining 10 patients received folic acid supplementation. Folic acid supplementation resulted in a significant increase of folate and decrease of tHcy, whereas both parameters remained unchanged in the placebo group.Conclusions: Hyperhomocysteinemia is present in 15.5% of children receiving long-term AED treatment. Multidrug treatment and long duration of therapy enhance the risk for hyperhomocysteinemia. Folic acid supplementation significantly reduces tHcy. We recommend assessment of serum folate and plasma tHcy in children receiving AEDs.

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

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

Cited by 76 publications

References 35 publications

Drugs–nutrient interactions: a potential problem during adolescence

Drugs–nutrient interactions: a potential problem during adolescence

Critical Evaluation of Antiepileptic Drugs in Epileptic Pregnant Women - Hungarian Experiences

Hyperhomocysteinemia in Children Treated with Antiepileptic Drugs Is Normalized by Folic Acid Supplementation

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