Formation of A Novel Purine Metabolite through CYP3A4 Bioactivation and Glutathione Conjugation.
| Autor: | Apuy JL, Xiang C, Franc S, Hegde SG, Hubbard R, Zhao J, Moghaddam MF; Celgene Corporation, 10300 Campus Point Dr, Suite 100, San Diego, CA 92121, USA. mmoghadd@celgene.com. |
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| Jazyk: | angličtina |
| Zdroj: | Drug metabolism letters [Drug Metab Lett] 2016; Vol. 10 (2), pp. 144-50. |
| DOI: | 10.2174/1872312810666160511150558 |
| Abstrakt: | 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. |
| Databáze: | MEDLINE |
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