VPA-induced neural tube defects in mice. I. Altered metabolism of sulfur amino acids and glutathione.
Valproate (VPA) has been shown to induce neural tube defects (NTDs) in humans and mice, but the mechanism of action has not been elucidated. Folate supplementation has been reported to prevent the defect. It was the aim of our experiment to reveal effects of VPA and of folate coadministration on amino acid metabolism in an NTD mouse model. After treating pregnant mice intraperitoneally with 2.1 mmol VPA/kg body weight, plasma homocysteine concentrations were found to be increased. Coadministration of 4 mg/kg folate decreased this level. Plasma methionine levels were reduced under both experimental conditions. Fifteen min after treating mice with 3 mmol VPA/kg body weight, hepatic levels of both S-adenosylmethionine (SAM) and S-adenosylhomocysteine were found to be increased by +175% and +348%, respectively; but the levels had normalized again 30 min after VPA injection. Simultaneously, plasma methionine and serine levels had decreased by -43% and -51%, respectively, while homocysteine and cysteine increased by +71% and +81%, respectively. Reduced glutathione (GSH) decreased by -45%, but total glutathione did not change. These changes were statistically significant, and they occurred dose-dependently. We proposed that VPA induces methionine deficiency inhibition of folate metabolism and homocysteine remethylation, increase in aminothiols, and suppression of the GSH system in maternal blood within 1 h after application. These changes may be responsible for the teratogenic potential of VPA. Folate may prevent NTDs by changing homocysteine catabolism.
Hishida
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Abteilung Toxikologie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Germany.
Nau
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D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D005260:Female; D005492:Folic Acid / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D006710:Homocysteine / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008715:Methionine / Q000378:metabolism; D051379:Mice; D009436:Neural Tube Defects / Q000139:chemically induced*; D011247:Pregnancy; D014635:Valproic Acid / Q000633:toxicity*
D000596:Amino Acids; D000927:Anticonvulsants; D006710:Homocysteine; D014635:Valproic Acid; D005492:Folic Acid; D008715:Methionine; D005978:Glutathione