THE METHYLFOLATE AXIS IN NEURAL-TUBE DEFECTS - IN-VITRO CHARACTERIZATION AND CLINICAL INVESTIGATION

We have investigated various micronutrients important to folate metabo lism in women with two previous neural tube defect (NTD)-affected preg nancies. Results suggest the disposition of plasma 5-methyltetrahydrof olate (5CH(3)-H(4)PteGlu) with respect to dietary intake may differ fr om that of the control population. It appears that to achieve a given plasma level of 5CH(3)-H(4)PteGlu, the population with a history of NT D pregnancies needs to take in more dietary folate than controls. We d iscuss 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 5CH( 3)-H(4)PteGlu, has been investigated in a rat model using liver homoge nate. The anticonvulsant drug (ACD) carbamazepine was found to inhibit the reaction in terms of a reduced V-max and increased K-m. Inhibitio n approaching maximal was found to occur at therapeutic levels of ACD. Various potential inhibitory sites along the methylfolate axis are co nsidered and possible relationships to congenital malformations discus sed. We describe folate and one carbon metabolism in relation to poten tial 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 h ow 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 thymi ne. (C) 1994 Academic Press, Inc.