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 suggested that affected individuals may have a genetically-determined defect of microsomal epoxide hydrolase. The aim of this study was to determine whether a single genetic mutation or pattern of mutations could be used to predict individual susceptibility to carbamazepine-hypersensitivity. DNA was isolated from 10 carbamazepine-hypersensitive patients and 10 healthy volunteers. The patients had developed various forms of toxicity with carbamazepine, including toxic epidermal necrolysis, Stevens-Johnson syndrome, hepatitis and pneumonitis. The technique of polymerase chain reaction single-strand conformation polymorphism analysis (PCR-SSCP) was used to screen for mutations in all nine exons of the microsomal epoxide hydrolase gene. Any new mutations detected by this method were characterised by direct sequencing of the DNA. In addition, in the most severely affected patient, we sequenced all nine exons of the gene. There was a higher frequency of mutations in the hypersensitive group when compared with the controls, but there was no consistent mutation (or pattern of mutations) in the microsomal epoxide hydrolase gene which was common to the hypersensitive group. DNA sequencing of all nine exons of the microsomal epoxide hydrolase gene from the most severely affected patient showed the sequence to be "wild-type," 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 determinant of the predisposition to carbamazepine hypersensitivity.
Green
V J
VJ
Department of Pharmacology and Therapeutics, University of Liverpool, U.K.
Pirmohamed
M
M
Kitteringham
N R
NR
Gaedigk
A
A
Grant
D M
DM
Boxer
M
M
Burchell
B
B
Park
B K
BK
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000009:adverse effects*; D002220:Carbamazepine / Q000009:adverse effects*; D004247:DNA / Q000032:analysis / Q000235:genetics; D004198:Disease Susceptibility; D004342:Drug Hypersensitivity / Q000201:enzymology* / Q000209:etiology / Q000235:genetics*; D004851:Epoxide Hydrolases / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D008861:Microsomes / Q000201:enzymology; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational
D000927:Anticonvulsants; D002220:Carbamazepine; D004247:DNA; D004851:Epoxide Hydrolases