Depression of immune competence by phenytoin and carbamazepine. Studies in vivo and in vitro
Sorrell, T.C.; Forbes, I.J.
Clinical and Experimental Immunology 20(2): 273-285
1975
ISSN/ISBN: 0009-9104 PMID: 1212810 Document Number: 89052
Because the occurrence of Hodgkin's disease and other lymphomas has been documented in a significant number of patients treated with the anticonvulsive drug, phenytoin sodium and other hydantoins, the effect of such drugs on the immune system was studied. Depression of .gtoreq. 1 parameter of cellular and/or humoral immune responses was found in 60% of general hospital patients treated with phenytoin and 47% of patients treated with carbamazepine. Phenytoin-treated patients failed to manifest delayed hypersensitivity (DHS) reactions to common antigens, and to make antibody to Salmonella typhi and tetanus toxoid. Serum levels of IgA [immunoglobulin A] and IgM, DNA synthesis in circulating leukocytes, and phytohemagglutinin (PHA) induced DNA synthesis were also low. Depression of IgA, DHS reactivity and antibody responsiveness to S. typhi apparently developed after the commencement of phenytoin therapy in a study of 11 patients. The presence of immunological defects was independent of the dosage of drug, its serum concentration, the duration of therapy and the sex of the subject. Immunosuppression was probably the result of a direct effect of phenytoin on the metabolism of lymphoid cells. Carbamazepine had a similar but less potent direct effect. Pharmacological concentrations of phenytoin caused a significant depression of DNA synthesis in PHA-stimulated and non-stimulated blood cell cultures in vitro. High concentrations in addition caused depression of cell counts, lymphocyte blastogenesis, DNA and protein synthesis. Phenytoin was not cytocidal at concentrations of up to 125 .mu.g/ml. Depression of DNA synthesis by phenytoin was maximal when phenytoin was added within 4-8 h of the addition of PHA. PHA-induced DNA synthesis was not significantly affected by pre-incubation with phenytoin. In vivo, the presence of immunological defects was not related to phenytoin-induced folic acid deficiency. High concentrations of carbamazepine, but not phenobarbitone or diazepam caused a significant depression of PHA-stimulated DNA synthesis in blood cell cultures. Immunosuppression is apparently a common side-effect of phenytoin therapy, and lymphoma is rare. In the presence of phenytoin-induced immunosuppression, other factors are probably required to induce the formation of lymphoma.