GENETIC-ANALYSIS OF MICROSOMAL EPOXIDE HYDROLASE IN PATIENTS WITH CARBAMAZEPINE HYPERSENSITIVITY

Carbamazepine therapy is occasionally complicated by hypersensitivity reactions, the mechanism of which is poorly understood. It has been su ggested that affected individuals may have a genetically-determined de fect of microsomal epoxide hydrolase. The aim of this study was to det ermine whether a single genetic mutation or pattern of mutations could be used to predict individual susceptibility to carbamazepine-hyperse nsitivity. DNA was isolated from 10 carbamazepine-hypersensitive patie nts and 10 healthy volunteers. The patients had developed various form s of toxicity with carbamazepine, including toxic epidermal necrolysis , Stevens-Johnson syndrome, hepatitis and pneumonitis. The technique o f polymerase chain reaction single-strand conformation polymorphism an alysis (PCR-SSCP) was used to screen for mutations in all nine exons o f the microsomal epoxide hydrolase gene. Any new mutations detected by this method were characterised by direct sequencing of the DNA. In ad dition, in the most severely affected patient, we sequenced all nine e xons of the gene. There was a higher frequency of mutations in the hyp ersensitive group when compared with the controls, but there was no co nsistent mutation (or pattern of mutations) in the microsomal epoxide hydrolase gene which was common to the hypersensitive group. DNA seque ncing of all nine exons of the microsomal epoxide hydrolase gene from the most severely affected patient showed the sequence to be ''wild-ty pe,'' when compared to the previously published sequences. The results of this study suggest that a single mutation within the coding region of the microsomal epoxide hydrolase gene cannot be the sole determina nt of the predisposition to carbamazepine hypersensitivity.