Predisposition to Phenytoin Hepatotoxicity Assessed in Vitro

Stephen P. Spielberg, Gary B. Gordon, David A. Blake, Daniel A. Goldstein, H. Franklin Herlong, Stephen P. Spielberg

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214 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)722-727
Number of pages6
JournalNew England Journal of Medicine
Issue number13
StatePublished - Sep 24 1981
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)


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