ArticleMolecular pharmacology2013
Molecular insights into microbial β-glucuronidase inhibition to abrogate CPT-11 toxicity.
Article in Molecular pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 129 citations in OpenAlex.
- Recent advances and clinical relevance of microbiome dynamics in health and disease.Gut microbes · 2026Review
- The Gut Microbiome Dependency Continuum in Drug Discovery: A Unified Pharmacology Framework Linking Clinical Drugs, Natural Products, and Engineered Microbial Therapeutics.Biotech (Basel (Switzerland)) · 2026Review
- Synergistic Interactions Between Gut and Intratumoral Microbiota: A New Perspective on the Oncogenesis and Treatment of Colorectal Cancer.Digestive diseases and sciences · 2026Review
- Metabolism-Driven Modulation by the Human Microbiota: Implications for Cancer Therapy and Emerging Strategies.Advances in experimental medicine and biology · 2026Review
- Microbiome dysbiosis and chemotherapy resistance in acute myeloid leukemia (AML).NPJ biofilms and microbiomes · 2025Review
- Emerging gut microbial glycoside hydrolase inhibitors.RSC chemical biology · 2025Review
- Natural Flavonoids from Licorice as Potent Inhibitors of β-Glucuronidase Elucidated Through Computational Studies.Molecules (Basel, Switzerland) · 2025Article
- A Small-Molecule Inhibitor of Gut Bacterial Urease Protects the Host from Liver Injury.ACS chemical biology · 2025Article
- Rifaximin alleviates irinotecan-induced diarrhea in mice model.Annals of medicine · 2024Article
- The role of gut microbial β-glucuronidases in carcinogenesis and cancer treatment: a scoping review.Journal of cancer research and clinical oncology · 2024Article
- Gut Microbiota Disruption in Hematologic Cancer Therapy: Molecular Insights and Implications for Treatment Efficacy.International journal of molecular sciences · 2024Review
- Article
- A New Paradigm in the Relationship between Gut Microbiota and Breast Cancer: β-glucuronidase Enzyme Identified as Potential Therapeutic Target.Pathogens (Basel, Switzerland) · 2023Review
- Human Gut Microbiota and Drug Metabolism.Microbial ecology · 2023Review
- Role of the gut microbiota in anticancer therapy: from molecular mechanisms to clinical applications.Signal transduction and targeted therapy · 2023Review
- Targeting the human gut microbiome with small-molecule inhibitors.Nature reviews. Chemistry · 2023Review
- Characterizing the metabolic effects of the selective inhibition of gut microbial β-glucuronidases in mice.Scientific reports · 2022Article
- Article
- Pharmacological hypothesis: A recombinant probiotic for taming bacterial β-glucuronidase in drug-induced enteropathy.Pharmacology research & perspectives · 2022Article
- Microbiota in health and diseases.Signal transduction and targeted therapy · 2022Review
3 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Bacterial β-glucuronidases expressed by the symbiotic intestinal microbiota appear to play important roles in drug-induced epithelial cell toxicity in the gastrointestinal (GI) tract. For the anticancer drug CPT-11 (irinotecan) and the nonsteroidal anti-inflammatory drug diclofenac, it has been shown that removal of the glucuronide moieties from drug metabolites by bacterial β-glucuronidases in the GI lumen can significantly damage the intestinal epithelium. Furthermore, selective disruption of bacterial β-glucuronidases by small molecule inhibitors alleviates these side effects, which, for CPT-11 {7-ethyl-10-[4-(1-piperidino)-1-piperidino]}, can be dose limiting. Here we characterize novel microbial β-glucuronidase inhibitors that inhibit Escherichia coli β-glucuronidase in vitro with Ki values between 180 nM and 2 μM, and disrupt the enzyme in E. coli cells, with EC50 values as low as 300 nM. All compounds are selective for E. coli β-glucuronidase without inhibiting purified mammalian β-glucuronidase, and they do not impact the survival of either bacterial or mammalian cells. The 2.8 Å resolution crystal structure of one inhibitor bound to E. coli β-glucuronidase demonstrates that it contacts and orders only a portion of the "bacterial loop" present in microbial, but not mammalian, β-glucuronidases. The most potent compound examined in this group was found to protect mice against CPT-11-induced diarrhea. Taken together, these data advance our understanding of the chemical and structural basis of selective microbial β-glucuronidase inhibition, which may improve human drug efficacy and toxicity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.