Phenytoin-induced depletion of folate in rats originates in liver and involves a mechanism that does not discriminate folate form.
The anticonvulsant phenytoin causes a decrease in plasma concentrations of folate in epileptic patients. The mechanism underlying this depletion is unknown. To study this mechanism, phenytoin was administered to rats by addition to the diet (3 g phenytoin/kg diet) for up to 8 wk. At selected times during phenytoin administration (0, 3, 7, 10, 14, 28, 42 and 56 d), the composition of the folate pools of intestinal mucosa, liver, bile and brain was determined. The 0-d administration served as the control group. The controls were fed the same diet without phenytoin for the eight weeks of the experiment. Phenytoin administration had minimal effect on either the folate concentration or the composition of the folate pool in intestinal mucosa. Phenytoin administration did, however, cause a depletion of total hepatic folate to about 50% of control, causing the pentaglutamate derivatives of each of the pteridine derivatives to decline rapidly, with the formyl and dihydro derivatives of the pteridine moiety falling more rapidly than the methyl and methylene + tetrahydro derivatives. The monoglutamate of the methylene + unsubstituted tetrahydro derivative increased significantly with time of phenytoin treatment. The mono- and di-glutamate derivatives of the methyltetrahydrofolate increased transiently and significantly in the bile, and the polyglutamate chain length increased significantly in the brain with time of phenytoin treatment. We conclude that phenytoin inhibits the formation of polyglutamyl folates in rat liver.
Carl
G F
GF
Medical Research Service, VA Medical Center, Augusta, GA 30904, USA.
Hudson
F Z
FZ
McGuire
B S
BS
D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D001646:Bile / Q000737:chemistry / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D004032:Diet; D004305:Dose-Response Relationship, Drug; D005492:Folic Acid / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D005971:Glutamates / Q000378:metabolism; D007413:Intestinal Mucosa / Q000737:chemistry / Q000187:drug effects; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D010672:Phenytoin / Q000008:administration & dosage / Q000494:pharmacology*; D011621:Pteridines / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D000927:Anticonvulsants; D005971:Glutamates; D011621:Pteridines; D010672:Phenytoin; D005492:Folic Acid