Gennis M A, Vemuri R, Burns E A, Hill J V, Miller M A, Spielberg S P
Department of Medicine, University of Wisconsin School of Medicine, Milwaukee.
Am J Med. 1991 Dec;91(6):631-4. doi: 10.1016/0002-9343(91)90216-k.
Therapy with anticonvulsants such as phenytoin, phenobarbital, and carbamazepine can be complicated by severe hypersensitivity reactions. Previous work has suggested that the predisposition to such reactions is based on an inherited abnormality in the detoxification of reactive metabolites of the drugs. However, there are no reports of familial occurrence of the reactions in the literature. In the current study, we examined a family in which three siblings developed hypersensitivity reactions to phenytoin, confirming the inheritance of a predisposition to the reactions. Detoxification of reactive metabolites of the anticonvulsants was studied in cells from the patients and their siblings.
Three siblings from a family of 12 siblings developed hypersensitivity reactions to phenytoin characterized by fever, rash, lymphadenopathy, and anicteric hepatitis. All recovered completely after discontinuation of treatment. One sibling tolerated phenobarbital without toxic sequelae. Peripheral blood mononuclear cells from the three patients and five additional siblings who had never taken anticonvulsants were exposed to oxidative metabolites of phenytoin, phenobarbital, and carbamazepine generated by a hepatic microsomal drug-metabolizing system in vitro. The toxicity of metabolites in the cells from the siblings was compared with that in cells from control subjects.
Cells from each of the patients who had experienced a hypersensitivity reaction exhibited increased toxicity from metabolites of phenytoin and carbamazepine, while the cellular response to metabolites of phenobarbital was within normal limits. Cells from four of the other siblings showed an abnormal response to phenytoin metabolites, while cells from the final sibling detoxified phenytoin metabolites normally.
Our observations on the patients confirm the inherited nature of phenytoin hypersensitivity reactions in vivo. In vitro studies demonstrated abnormal metabolite detoxification in the patients and several of their siblings. The detoxification defect included metabolites of phenytoin and carbamazepine but not of phenobarbital. A family history of a drug hypersensitivity reaction should alert physicians to the probability of a markedly increased risk of an adverse reaction in family members. In vitro assays to confirm adverse reaction risks may ultimately be able to provide individualized risk assessment for patients who must take anticonvulsants.
使用苯妥英钠、苯巴比妥和卡马西平等抗惊厥药物进行治疗时，可能会因严重的过敏反应而变得复杂。先前的研究表明，此类反应的易感性基于药物活性代谢产物解毒过程中的遗传异常。然而，文献中尚无关于此类反应家族性发生的报道。在本研究中，我们对一个家庭进行了研究，该家庭中有三名兄弟姐妹对苯妥英钠发生了过敏反应，证实了对该反应易感性的遗传。我们对患者及其兄弟姐妹的细胞中抗惊厥药物活性代谢产物的解毒情况进行了研究。
一个有12名兄弟姐妹的家庭中有三名兄弟姐妹对苯妥英钠发生了过敏反应，其特征为发热、皮疹、淋巴结病和无黄疸型肝炎。停药后所有患者均完全康复。一名兄弟姐妹耐受苯巴比妥且无毒性后遗症。来自三名患者以及另外五名从未服用过抗惊厥药物的兄弟姐妹的外周血单核细胞，在体外被肝微粒体药物代谢系统产生的苯妥英钠、苯巴比妥和卡马西平的氧化代谢产物所暴露。将这些兄弟姐妹细胞中代谢产物的毒性与对照受试者细胞中的毒性进行比较。
经历过过敏反应的每位患者的细胞，对苯妥英钠和卡马西平代谢产物的毒性均增加，而对苯巴比妥代谢产物的细胞反应在正常范围内。其他四名兄弟姐妹的细胞对苯妥英钠代谢产物表现出异常反应，而最后一名兄弟姐妹的细胞对苯妥英钠代谢产物的解毒正常。
我们对患者的观察证实了体内苯妥英钠过敏反应的遗传性。体外研究表明患者及其几名兄弟姐妹存在代谢产物解毒异常。解毒缺陷包括苯妥英钠和卡马西平的代谢产物，但不包括苯巴比妥的代谢产物。药物过敏反应的家族史应提醒医生，家庭成员发生不良反应的风险可能会显著增加。用于确认不良反应风险的体外检测最终可能能够为必须服用抗惊厥药物的患者提供个性化的风险评估。
