The mechanism of amantadine acetylation
Notice bibliographique
Résumé
Amantadine is an irnportant drug in the treatment of and prophylaxis against influenza A virus infection anci in the treatment of Parkinson's disease.Amantadine was approved for the preceding diseases in the late 1960s and was initially reported not to be subject to metabolism.However, in 1985, N-acetylation was identif,red as a minor metabolic pathway for amantadine.No further study in this area was conducted.Therefore the mechanism that rnediates the acetylation of amantadine remained to be described.This thesis work has investigated how amantadine is acetylated.The hypotheses of this project were divided into two parts: 1.The N-acetyltransferases, NATI and NAT2, do not catalyze the acetylation of amantadine; 2. The enzyme, spermidine/spermine Nr- acetyltransferase (SSAT), that catalyzes the acetylation of spermidine and spermine is responsible for catalyzing the acetylation of amantadine when this enzlnne is induced or overexpressed.The first srudy used NATI and NAT2 enzymes from three different sources, rat liver, rabbit liver, and human recombinant wild type NATI and NAT2, incubated with their selective substrates p-aminobenzoic acid (PABA) and sulfamethazine (SMZ), respectively.The addition of amantadine to the selective subtrates in the same incubation medium did not inhibit their acetylation.Amantadine incubated in the absence of the substrates also was notacetylated.These results suggested that neither NAT I nor NAT2 were responsible for amantadine acetylation.The second study involved transgenic mice overexpressing SSAT and injected with amantadine.All mice excreted acetylamantadine in their urine.Controls of the same strain not overexpressing SSAT did not excrete acetylamantadine.In vitro experiments using the cytosolic liver fraction as the source of SSAT demonstrated that amantadine V could inliibit spermidine acetylation competitively.Incubation of amantadine with an acetyl-coenzynte A. regenerating system and transgenic mouse liver as the cytosolic source of SSAT produced modest amounts of acetylamantadine.Co-incubation of amantadine and the NAT2 selective substrate SMZ inhibited production of acetylamantadine.The selective NAT2 substrate, SMZ, but not the NATI-selective substrate PABA, modestly inhibited spermidine acetylation.In conclusion, the data support the hypothesis that amantadine acetylation is catalyzed by SSAT and may be a specific substrate for this enzyme.These frndings indicate that SSAT may be a drug acetylation pathway when induced or overexpressed and may contribute to NAT2 selective substrate acetylation. VI ACKNOWLEDGBiVIENTSFirst of all I would like to express my sincere thanks to Dr. Daniel Sitar for providing me the opportunity to pursue a scientific carrier.As a supervisor, he offered excellent mentorship, guidance, and shared his insights into doing science.I greatly appreciated his generous availability of time to discuss the project and all its complexities.His enthusiasm for science always amazed me and provided the motivation to continue the pursuit of scientific insight.As a friend, he appreciated some of the hurdles that I faced in everyday life and always tried to help if he could, and these gestures will never be forgotten.The Department of Pharmacology and Therapeutics as a whole provided a great atmosphere for learning and personal development.All professors are praise wortliy in their generous availability of time for the students when they require it.Time is the greatest gift a professor can give a sfudent and I greatly appreciated all the discussions that I had with different professors.
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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 | 0,001 | 0,000 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
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 ».