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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.
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.
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.(Arch Dermatol. 1995;131:544-551)
Wolkenstein P, Charue D, Laurent P, Revuz J, Roujeau J, Bagot M. Metabolic Predisposition to Cutaneous Adverse Drug Reactions: Role in Toxic Epidermal Necrolysis Caused by Sulfonamides and Anticonvulsants. Arch Dermatol. 1995;131(5):544–551. doi:10.1001/archderm.1995.01690170046006
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