In-vitro lymphocyte toxicity to a phenytoin metabolite in phenytoin induced cutaneous adverse drug eruptions

BACKGROUND: Phenytoin, one of the most commonly used antiepileptic drug, is associated with a wide spectrum of adverse drug eruptions. It is metabolized by the hepatic microsomal enzymes. The intermediate metabolites are arene oxides which accumulate due to deficiency of the enzyme epoxide hydrolase. These are postulated to be associated with phenytoin induced hepatotoxicity and antiepileptic hypersensitivity syndrome.
AIM: We tried to correlate the in vitro lymphocyte toxicity of arene oxide metabolites with phenytoin induced drug eruptions and hence develop it as a predictive test for the same.
METHODS: Clinically diagnosed cases of phenytoin induced drug eruptions were selected in this hospital based study. Lymphocytes from the subjects and controls were exposed to the phenytoin metabolites generated by a murine hepatic microsomal system. The toxicity was assayed by trypan blue dye exclusion test. The results were analyzed by a linear orthogonal curve and were compared for the subject and control.
RESULTS: The results showed increased toxicity to lymphocytes from the patients when compared to those from controls. The toxicity was directly proportional to the severity of the drug eruption.
CONCLUSION: In vitro lymphocyte cytotoxicity to phenytoin metabolites tested in this animal system could possibly predict phenytoin induced drug eruptions.

Keywords
Phenytoin, adverse drug eruption, arene oxide metabolites, epoxide hydrolase, in vitro lymphocyte toxicity test