Predisposition to Phenytoin Hepatotoxicity Assessed in Vitro

Arene oxide metabolites of phenytoin may be involved in the pathogenesis of drug-induced hepatotoxicity. We examined individual susceptibility to toxicity from such metabolites by exposing human lymphocytes to metabolites generated by a murine hepatic microsomal system. Cells from 17 controls showed no toxicity at concentrations of phenytoin from 31 to 125 μM. Cells from three patients with phenytoin hepatotoxicity manifested dose-dependent toxicity from the metabolites. Phenytoin alone was not toxic to cells. The patients' dose-response curves resembled the response of control cells in which epoxide hydrolase (a detoxification enzyme for arene oxides) was inhibited. Detoxification of non-arene oxide metabolites (e.g., of acetaminophen) was normal in patients' cells. Cells from parents of two patients had intermediate responses. Cells from a sibling of one patient showed no toxicity; a sibling of another patient had a response similar to that of the patient. A heritable defect in response to arene oxides thus may predispose some patients to phenytoin hepatotoxicity. (N Engl J Med. 1981; 305:722–7.) SINCE its introduction for the treatment of seizures in 1938, phenytoin has remained one of the most widely used anticonvulsants. Perhaps the most severe and potentially life-threatening side effect of the drug is a rare idiosyncratic reaction characterized by fever, skin rash, hepatotoxicity, lymphadenopathy (pseudolymphoma), and various hematologic responses, including leukocytosis, eosinophilia, hemolytic anemia, and even more rarely pancytopenia.^1,2 The syndrome, which typically occurs several weeks after therapy is started, can present with many combinations of symptoms; it has been clinically mistaken for infectious mononucleosis, rubella, collagen vascular diseases, or lymphoma.^{1 2 3 4 5 6} Patients presenting with overt hepatocellular dysfunction appear to have.