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Amoxapine Demonstrates Incomplete Inhibition of β-Glucuronidase Activity from Human Gut Microbiota
Yang W.2; Wei B.2; Yan R.2
2018
Source PublicationSLAS Discovery
ISSN24725560 24725552
Volume23Issue:1Pages:76-83
Abstract

Amoxapine has been demonstrated to be a potent inhibitor of Escherichia coli β-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 β-glucuronidase activity in gut microbiota from 10 healthy individuals and their pool (pool, 11.9%; individuals, 3.6%−54.4%) with IC >100 µM and potent inhibition toward E. coli β-glucuronidase (IC = 0.34 µM). p-Nitrophenol formation from p-nitrophenyl-β-D-glucuronide by pooled and individual gut microbiota fitted classical Michaelis-Menten kinetics, showing similar affinity (K = 113–189 µM) but varied catalytic capability (V = 53–556 nmol/h/mg). Interestingly, amoxapine showed distinct inhibitory effects (8.7%–100%) toward β-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 β-glucuronidase inhibition in humans, highlighting the necessity of using a human gut microbiota community for drug screening.

KeywordAmoxapine Bacterial Isolates Cpt-11–induced Toxicity Human Gut Microbiota Β-glucuronidase Inhibition
DOIhttp://doi.org/10.1177/2472555217725264
URLView the original
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology ; Biotechnology & Applied Microbiology ; Chemistry
WOS SubjectBiochemical Research Methods ; Biotechnology & Applied Microbiology ; Chemistry, Analytical
WOS IDWOS:000418556100008
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Cited Times [WOS]:4   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.UM Zhuhai Research Institute
2.Universidade de Macau
Recommended Citation
GB/T 7714
Yang W.,Wei B.,Yan R.. Amoxapine Demonstrates Incomplete Inhibition of β-Glucuronidase Activity from Human Gut Microbiota[J]. SLAS Discovery,2018,23(1):76-83.
APA Yang W.,Wei B.,&Yan R..(2018).Amoxapine Demonstrates Incomplete Inhibition of β-Glucuronidase Activity from Human Gut Microbiota.SLAS Discovery,23(1),76-83.
MLA Yang W.,et al."Amoxapine Demonstrates Incomplete Inhibition of β-Glucuronidase Activity from Human Gut Microbiota".SLAS Discovery 23.1(2018):76-83.
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