Insufficient parahydroxylation as a cause of diphenylhydantoin toxicity

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Abstract
Diphenylhydantoin toxicity at a commonly used dosage of approximately 4.0 mg/kg of body weight was observed in 2 of 4 siblings and the mother of a family who were otherwise in good health. A dosage of 1.4 mg/kg of body weight did not cause toxicity. Metabolic studies revealed that the cause of toxicity was accumulation of unmetabolized drug caused by insufficient parahydroxylation of diphenylhydantoin in the liver. It is suggested that the enzymatic factor that was deficient in these individuals was involved in parahydroxylation of phenol primarily in the diphenylhydantoin structure, since the barbiturates and phenylalanine were metabolized normally. The deficiency was a low ceiling of the activity of the enzyme rather than total lack of it, and it appears to be a specific genetically determined deficiency.