Biochemical Lesion in Dilantin-Induced Erythroid Aplasia

Abstract

Abstract Clinical and biochemical studies are reported in a patient who developed pure red cell aplasia after 2 years therapy with Dilantin but in whom aplasia could subsequently be induced with 4-5 Gm. of the drug. Recovery occurred regularly when the drug was discontinued. The administration of 1500 ml. of patient’s plasma obtained during the aplastic phase to a normal volunteer with Dilantin had no effect on the recipient’s reticulocyte count, number of nucleated red cells in his bone marrow, or Fe59 clearance. Attempts to demonstrate binding of gamma globulin to the patient’s nucleated red cells in the presence of Dilantin by immunofluorescence technic were unsuccessful. Dilantin, in a concentration of 20 µg./ml. in vitro, caused significant inhibition of the uptake of C14 formate, glycine, adenine, orotic acid, and uridine into DNA but not into RNA of patient’s bone marrow studied when fully recovered. There was no effect on the uptake of deoxyuridine or thymidine. The Dilantin effect was specific to the erythroid cells as shown by radioautographic studies and by the absence of inhibition when these cells were absent from the bone marrow. Vitamin B12 and folinic aci dgiven to the patient in large doses did not reverse the hematologic effects of Dilantin. The daily intravenous administration of all four deoxyribonucleosides, deoxyadenosine, deoxyguanosine, deoxycytidine and thymidine had a suggestive, but not clear-cut, effect. In an effort to examine a possible relationship of the pure red cell aplasia in this patient to riboflavin metabolism, the patient was started simultaneously on Dilantin and riboflavin. Dilantin was now without effect. However, the patient remains refractory to Dilantin a year after riboflavin was discontinued. It is concluded that Dilantin exerted its toxic effect in this patient by specifically inhibiting DNA synthesis in erythroid cells probably at the step of deoxyribotide formation. The role of riboflavin in the development of resistance to the toxic effect of Dilantin in this patient remains uncertain.