Formation of A Novel Purine Metabolite through CYP3A4 Bioactivation and Glutathione Conjugation.
Drug Metab Lett
; 10(2): 144-50, 2016.
Article
en En
| MEDLINE
| ID: mdl-27165340
BACKGROUND: The study of novel sites of metabolism is important in understanding new mechanisms of biotransformation of a particular moiety by metabolic enzymes. This information is valuable in designing metabolically-stable compounds with drug-like properties. It may also provide insights into the existence of active and reactive metabolites. METHODS: We utilized small scale incubations to generate adequate amounts of the metabolite of interest. After purification, LC-MS/MS and Proton Nuclear Magnetic Resonance (1H-NMR) were utilized to unequivocally assign the novel site of glutathione conjugation on the purine ring system. RESULTS: A proposed novel site of glutathione conjugation was investigated on a diaminopurine-containing molecule. It was demonstrated that the formation of the glutathione conjugate at the C-6 position of the purine ring system was due to the bioactivation of the compound to a di-imine intermediate by CYP3A4, followed by the nucleophilic addition of glutathione. CONCLUSION: S-glutathionylation at C-6 position of a purine was proven unequivocally. This previously unreported mechanism constitutes a novel biotransformation for purines.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Purinas
/
Cromatografía Liquida
/
Citocromo P-450 CYP3A
/
Glutatión
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Drug Metab Lett
Asunto de la revista:
FARMACOLOGIA
/
METABOLISMO
Año:
2016
Tipo del documento:
Article
Pais de publicación:
Emiratos Árabes Unidos