The methylfolate axis in neural tube defects: in vitro characterisation and clinical investigation.
We have investigated various micronutrients important to folate metabolism in women with two previous neural tube defect (NTD)-affected pregnancies. Results suggest the disposition of plasma 5-methyltetrahydrofolate (5CH3-H4PteGlu) with respect to dietary intake may differ from that of the control population. It appears that to achieve a given plasma level of 5CH3-H4PteGlu, the population with a history of NTD pregnancies needs to take in more dietary folate than controls. We discuss this in the context of a potential lesion at or upstream from 5,10-methylenetetrahydrofolate reductase (MTHFR). This metabolic axis, which is responsible for the multienzymic conversion of PteGlu to 5CH3-H4PteGlu, has been investigated in a rat model using liver homogenate. The anticonvulsant drug (ACD) carbamazepine was found to inhibit the reaction in terms of a reduced Vmax and increased Km. Inhibition approaching maximal was found to occur at therapeutic levels of ACD. Various potential inhibitory sites along the methylfolate axis are considered and possible relationships to congenital malformations discussed. We describe folate and one carbon metabolism in relation to potential NTD lesion sites, not only in the light of present findings, but with respect to the published findings of other workers. Based on our hypothesis that an NTD lesion exists upstream from MTHFR, we expound how pteroylmonoglutamate supplementation may protect against NTD (i) by reducing endotoxic homocysteine and (ii) through inhibiting MTHFR (as do dihydrofolates) and thus diverting one carbon units into DNA thymine.
Lucock
M D
MD
Department of Clinical Medicine, Leeds General Infirmary, United Kingdom.
Wild
J
J
Schorah
C J
CJ
Levene
M I
MI
Hartley
R
R
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D009436:Neural Tube Defects / Q000209:etiology*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013763:Tetrahydrofolates / Q000097:blood*
D000927:Anticonvulsants; D013763:Tetrahydrofolates; D006710:Homocysteine; D005492:Folic Acid; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); C005984:5-methyltetrahydrofolate