Metabolic predisposition to cutaneous adverse drug reactions. Role in toxic epidermal necrolysis caused by sulfonamides and anticonvulsants.
METHODS
Cutaneous adverse drug reactions (ADRs) have been hypothesized to have a metabolic basis. Our aim was to identify detoxification defects involved in toxic epidermal necrolysis and other severe cutaneous ADRs. Lymphoid cells of 33 patients with cutaneous ADRs were challenged with reactive metabolites generated from drugs by a microsomal oxidation system. To be precise in the detoxification defect involved in sulfonamide and anticonvulsant reactions, we challenged lymphoid cells from 11 patients (seven patients with sulfonamide ADRs and four patients with anticonvulsants ADRs) to menadione and formaldehyde. Menadione induces toxic effects by oxygen species; formaldehyde is detoxified by aldehyde dehydrogenase, oxidase, and reductase.


RESULTS
When the culprit drug was a sulfonamide or an anticonvulsant (used in 13 and 13 patients, respectively), the toxic effects of culprit drug-reactive metabolites toward patients' lymphoid cells were higher than toward controls'. First-degree relatives of four patients with sulfonamide- and phenobarbital-induced toxic epidermal necrolysis were also tested. In each family, a relative was more susceptible to culprit drug-reactive metabolites than were controls. After incubation with menadione, or formaldehyde, no difference in toxicity was found between patients' and controls' lymphoid cells.


CONCLUSIONS
Toxic epidermal necrolysis and other severe cutaneous ADRs to sulfonamides and anticonvulsant drugs may be linked to a highly specific defect in the detoxification of culprit drug-reactive metabolites. Our results suggest that this defect is constitutional and inherited and does not involve oxygen free radicals and/or aldehyde detoxification pathways.
Wolkenstein
P
P
Department of Dermatology, Hôpital Henri-Mondor, Créteil, France.
Charue
D
D
Laurent
P
P
Revuz
J
J
Roujeau
J C
JC
Bagot
M
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000009:adverse effects* / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D004198:Disease Susceptibility; D005260:Female; D005557:Formaldehyde / Q000378:metabolism / Q000633:toxicity; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D006801:Humans; D008221:Lymphoid Tissue / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D013262:Stevens-Johnson Syndrome / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000009:adverse effects* / Q000378:metabolism; D014812:Vitamin K / Q000378:metabolism / Q000633:toxicity
D000927:Anticonvulsants; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D014812:Vitamin K; D005557:Formaldehyde; D009249:NADP; D005954:Glucosephosphate Dehydrogenase