Investigating the Involvement of the Sulfotransferase Pathway in Drug-induced Skin Rash
Notice bibliographique
Résumé
Circumstantial evidence suggests that most idiosyncratic drug reactions are caused by chemically reactive metabolites of the drug that covalently binds to proteins. The skin is a major target of idiosyncratic reactions; however, drug metabolism in the skin is limited. One exception is the presence of relatively high sulfotransferase activity in human skin. For example, nevirapine-induced skin rash is caused by a reactive benzylic sulfate formed in the skin. The working hypothesis is that the serious skin rashes caused by other drugs involve reactive sulfate metabolites formed in the skin. Trimethoprim, lamotrigine, valdecoxib, and sertraline have the potential to produce reactive sulfate metabolites that may be responsible for drug-induced skin rash. Anti-drug antibodies against trimethoprim, lamotrigine, and valdecoxib were made to study covalent binding of the drug to proteins. Brown Norway rats were treated with these drugs, and their liver and skin proteins were immunoblotted to look for covalent binding. No covalent binding of any of these drugs was detected in the skin, but covalent binding of trimethoprim was detected in the liver. The immunoassay may not be sufficiently sensitive to detect covalent binding in the skin, or binding may be limited to human skin. The sulfates of hydroxy-trimethoprim and lamotrigine-N-oxide, which are metabolites of these drugs, were chemically synthesized, and both were found to be chemically reactive. Surprisingly, even hydroxy-trimethoprim itself had sufficient reactivity to covalently bind to proteins in vitro. Dr. Liu, our collaborator at the University of Toledo, tested whether hydroxy-trimethoprim, lamotrigine-N-oxide, hydroxy-valdecoxib or hydroxy-sertraline were substrates of human sulfotransferases. He found that lamotrigine-N-oxide was a substrate for several human sulfotransferases, while hydroxy-trimethoprim was only a substrate for the fetal sulfotransferase SULT1C4, and hydroxy-valdecoxib and hydroxy-sertraline were not substrates for human sulfotransferases. That implies that the rashes caused by valdecoxib and sertraline are not due to a sulfate metabolite. Given that hydroxy-trimethoprim is only a substrate for a fetal sulfotransferase but is weakly reactive, it may be responsible for trimethoprim rashes. The rash caused by lamotrigine is likely due to the N-O-sulfate; however, detection of covalent binding in skin would have strengthened the evidence for this hypothesis.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».