Genetic polymorphism of cytochrome P450 2C9 in diphenylhydantoin-induced cutaneous adverse drug reactions.

Abstract

Apart from allergic mechanisms, a lack or mutation of metabolic enzymes may cause adverse drug reactions. Patch testing has rarely been useful in cutaneous adverse drug reactions (CADRs) induced by diphenylhydantoin (DPH). Genetic polymorphisms leading to altered metabolic processes of cytochrome P(450) (CYP) 2C9, a main metabolic enzyme for DPH, may be the pathological mechanism for certain cases of DPH-induced CADRs. To examine the effects of an altered CYP2C9 variant, CYP2C9*3, on DPH-induced CADRs. Ten patients with DPH-induced CADRs were examined for CYP2C9 genetic polymorphisms. The results were compared with non-exposed controls and 39 neurological patients without DPH-induced CADRs despite exposure to DPH. The patients with DPH-induced CADRs were also patch tested with anti-epileptic drugs and the results were compared with 40 DPH-exposed and 58 non-exposed controls. A heterozygous CYP2C9*3 variant was found in three of the 10 DPH-induced CADR patients. The crude odds ratios (OR) of the patients compared with those of exposed and non-exposed controls were 167 and 71, respectively. Only one neurological patient, who had never taken DPH, showed the variant in both exposed (P=0.007) and non-exposed (P=0.001) controls. Positive patch-test results were displayed in three of the ten DPH-induced patients, but the patients with positive patch-test reactions to DPH differed from those with the CYP2C9*3 polymorphism. No patients and controls displayed a CYP2C9*2 variant. A CYP2C9*3 variant could play a role in the proportion of patients with DPH-induced CADRs that differ from patients with DPH-induced CADRs showing positive patch-test results.