Amoxapine Demonstrates Incomplete Inhibition of ß-Glucuronidase Activity from Human Gut Microbiota.
SLAS Discov
; 23(1): 76-83, 2018 01.
Article
en En
| MEDLINE
| ID: mdl-28809607
ABSTRACT
Amoxapine has been demonstrated to be a potent inhibitor of Escherichia coli ß-glucuronidase. This study aims to explore the factors causing unsatisfactory efficacy of amoxapine in alleviating CPT-11-induced gastrointestinal toxicity in mice and to predict the outcomes in humans. Amoxapine (100 µM) exhibited poor and varied inhibition on ß-glucuronidase activity in gut microbiota from 10 healthy individuals and their pool (pool, 11.9%; individuals, 3.6%-54.4%) with IC50 >100 µM and potent inhibition toward E. coli ß-glucuronidase (IC50 = 0.34 µM). p-Nitrophenol formation from p-nitrophenyl-ß-D-glucuronide by pooled and individual gut microbiota fitted classical Michaelis-Menten kinetics, showing similar affinity (Km = 113-189 µM) but varied catalytic capability (Vmax = 53-556 nmol/h/mg). Interestingly, amoxapine showed distinct inhibitory effects (8.7%-100%) toward ß-glucuronidases of 13 bacterial isolates (including four Enterococcus, three Streptococcus, two Escherichia, and two Staphylococcus strains; gus genes belonging to OTU1, 2 or 21) regardless of their genetic similarity or bacterial origin. In addition, amoxapine inhibited the growth of pooled and individual gut microbiota at a high concentration (6.3%-30.8%, 200 µM). Taken together, these findings partly explain the unsatisfactory efficacy of amoxapine in alleviating CPT-11-induced toxicity and predict a poor outcome of ß-glucuronidase inhibition in humans, highlighting the necessity of using a human gut microbiota community for drug screening.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Glicoproteínas
/
Microbioma Gastrointestinal
/
Glucuronidasa
/
Amoxapina
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
SLAS Discov
Año:
2018
Tipo del documento:
Article
País de afiliación:
China