Anticonvulsant-induced aplastic anemia: increased susceptibility to toxic drug metabolites in vitro

A 53-yr-old man sequentially developed aplastic anemia from phenytoin and carbamazepine. Both compounds undergo metabolism to potentially toxic arene oxide intermediates. We tested the hypothesis that the patient's adverse reactions were due to a defect in detoxification of such metabolites by challenging his peripheral lymphocytes with drug metabolites generated by a murine hepatic microsomal system in vitro. The patient's cell viability was normal in the absence of drugs. However, his cells showed greater toxicity from both phenytoin and carbamazepine metabolites than did controls. Toxicity was dependent on microsomes and NADPH. Intermediate toxicity was noted in cells from the patient's mother. The results provide the first evidence for a role of arene oxide drug metabolites in aplastic anemia in humans and suggest that enhanced susceptibility to toxicity may be based on an inherited abnormality in metabolite detoxification.