Margaretten N C, Hincks J R, Warren R P, Coulombe R A
Toxicol Appl Pharmacol. 1987 Jan;87(1):10-7. doi: 10.1016/0041-008x(87)90079-2.
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 alkaline elution. Concentrations of phenytoin considered therapeutic (10 and 20 micrograms/ml) and a dose considered acutely toxic (40 micrograms/ml) were used while carbamazepine levels of 8 micrograms/ml (therapeutic) and 10 and 16 micrograms/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 micrograms/ml phenytoin. Alkaline elution showed a slight but significant increase in DNA single-strand breaks of PBMC exposed to 40 micrograms/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.
从健康志愿者体内分离出人类外周血单核细胞（PBMC），并在体外将其暴露于苯妥英或卡马西平这两种广泛使用的抗癫痫药物（AED）中。本研究调查了这些药物对自然杀伤（NK）细胞活性和抗体依赖性细胞介导的细胞毒性（ADCC）的影响，这两种作用都被认为对预防肿瘤发生具有保护作用。此外，通过重力流碱性洗脱法研究了苯妥英对人类PBMC的遗传毒性。使用了被认为具有治疗作用的苯妥英浓度（10和20微克/毫升）以及一种被认为具有急性毒性的剂量（40微克/毫升），同时测试了卡马西平8微克/毫升（治疗剂量）以及10和16微克/毫升（急性毒性剂量）的水平。所有三种浓度的苯妥英均以剂量依赖性方式显著抑制NK细胞活性。在所研究的剂量水平下，卡马西平对NK细胞活性没有显著影响。与生理盐水相比，在卡马西平的稀释剂丙二醇中孵育显著降低了NK细胞活性。苯妥英还以剂量依赖性方式显著抑制NK细胞细胞毒性的干扰素增强作用。20和40微克/毫升的苯妥英显著降低了ADCC活性。碱性洗脱显示，暴露于40微克/毫升苯妥英18或72小时的PBMC的DNA单链断裂略有但显著增加。这些结果表明，苯妥英可能会在接受抗癫痫治疗的患者中诱导NK细胞和ADCC活性的明显免疫抑制，并且该药物具有遗传毒性副作用的可能性。苯妥英还可能通过与细胞DNA的直接相互作用和/或免疫抑制的间接机制增加肿瘤发生的可能性。
