Effects of Phenytoin and Carbamazepine on Human Natural Killer Cell Activity and Genotoxicity in Vitro

Authors

Nadine C. Margaretten, Utah State University
Jeffrey H. Hincks, Utah State University
Reed P. Warren, Utah State University
Roger A. Coulombe Jr., Utah State UniversityFollow

Document Type

Article

Journal/Book Title/Conference

Toxicology and Applied Pharmacology

Volume

87

Issue

1

Publisher

Elsevier

Publication Date

1987

First Page

10

Last Page

17

Abstract

Human peripheral blood mononuclear cells (PBMC) were isolated from healthy volunteers and exposed in vitro to phenytoin or carbamazepine, two widely used antiepileptic drugs (AED). This study investigated the effects of these drugs on natural killer (NK) cell activity and antibody-dependent cell-mediated cytotoxicity (ADCC), which are both thought to protect against developing neoplasms. Also, the genotoxicity of phenytoin on human PBMC was investigated by gravity-flow alkline elution. Concentrations of phenytoin considered therapeutic (10 and 20 μg/ml) and a dose considered acutely toxic (40 μg/ml) were used while carbamazepine levels of 8 μg/ml (therapeutic) and 10 and 16 μg/ml (acutely toxic) were tested. Phenytoin at all three concentrations significantly suppressed NK cell activity in a dose-dependent manner. Carbamazepine had no significant effect on NK cell activity at the dose levels studied. Incubation in propylene glycol, the diluent for carbamazepine, significantly decreased NK cell activity compared to saline. Phenytoin also significantly depressed interferon augmentation of NK cell cytotoxicity in a dose dependent manner. ADCC activity was significantly depressed with 20 and 40 μg/ml phenytoin. Alkaline elution showed a slight but significant increase in DNA single-strand breaks of PBMC exposed to 40 μg/ml phenytoin for 18 or 72 hr. These results show phenytoin may induce pronounced immunosuppression of NK cell and ADCC activity in patients receiving antiepileptic therapy and that this agent has a potential for genotoxic side effects. Phenytoin may also increase the potential for neoplasm development by a direct interaction with cellular DNA and/or an indirect mechanism by immunosuppression.

Comments

Originally published by Elsevier. Abstract available through remote link. Subscription required to access article fulltext.

Recommended Citation

Margaretten, N.C., J.H. Hincks, R.P. Warren and R.A. Coulombe, Jr. (1987). Effects of phenytoin and carbamazepine on human natural killer cell activity and genotoxicity in vitro. Toxicol. Appl. Pharmacol. 87:10-17.