In vitro screening of UGT2B10 in silico prioritized putative ligands from drugs used in the pediatric hematopoietic stem cell transplantation setting

Article Article scientifique Article In vitro screening of UGT2B10 in silico prioritized putative ligands from drugs used in the pediatric hematopoietic stem cell transplantation setting eng 2024-11 2024-12 author Bennani Yahia 0009-0001-2332-8100 Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.,Geneva Lausanne School of Pharmacy, University of Geneva, Geneva, Switzerland. 830927 Section des sciences pharmaceutiques (FARMA) author Ben Hassine Khalil Cansearch Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, Department of Pediatrics, Gynecology and Obstetrics, University of Geneva, Geneva, Switzerland.,Division of Pediatric Oncology and Hematology, Department of Women, Child and Adolescent, University Geneva Hospitals, Geneva, Switzerland. 779097 author Gencaslan Muhammed Yasin Geneva Lausanne School of Pharmacy, University of Geneva, Geneva, Switzerland. 849261 author Boudal-Khoshbeen Mary Cansearch Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, Department of Pediatrics, Gynecology and Obstetrics, University of Geneva, Geneva, Switzerland.,Division of Pediatric Oncology and Hematology, Department of Women, Child and Adolescent, University Geneva Hospitals, Geneva, Switzerland. 647871 Département de Pédiatrie, Gynécologie et Obstétrique (PETRI) author Samer Caroline Flora 0000-0001-8178-0616 Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.,Geneva Lausanne School of Pharmacy, University of Geneva, Geneva, Switzerland.,Swiss Center for Applied Human Toxicology, Geneva, Switzerland.,Faculty of Medicine, University of Geneva, Geneva, Switzerland. 105661 Département d'anesthésiologie, pharmacologie et soins intensifs (APSIC) author Ansari Djaberi Marc Georges Cansearch Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, Department of Pediatrics, Gynecology and Obstetrics, University of Geneva, Geneva, Switzerland.,Division of Pediatric Oncology and Hematology, Department of Women, Child and Adolescent, University Geneva Hospitals, Geneva, Switzerland. 61572 Département de Pédiatrie, Gynécologie et Obstétrique (PETRI) author Daali Youssef Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.,Geneva Lausanne School of Pharmacy, University of Geneva, Geneva, Switzerland.,Swiss Center for Applied Human Toxicology, Geneva, Switzerland.,Faculty of Medicine, University of Geneva, Geneva, Switzerland. 46042 Département d'anesthésiologie, pharmacologie et soins intensifs (APSIC) author Uppugunduri Satyanarayana Chakradhara Rao 0000-0002-8928-7049 Cansearch Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, Department of Pediatrics, Gynecology and Obstetrics, University of Geneva, Geneva, Switzerland.,Division of Pediatric Oncology and Hematology, Department of Women, Child and Adolescent, University Geneva Hospitals, Geneva, Switzerland.,Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India. 740772 e70011 10.1002/prp2.70011 39611692 2052-1707 PMC11605732 https://bpspubs.onlinelibrary.wiley.com/doi/10.1002/prp2.70011 UGT2B10 is a phase II drug metabolizing enzyme with limited information on its role in the metabolism of drugs, especially in the pediatric hematopoietic stem cell transplantation setting. Previously, we investigated UGT2B10's role through in silico analyses and prioritized acetaminophen (APAP), lorazepam (LOR), mycophenolic acid (MPA), and voriconazole N-oxide (VCZ N-oxide) for in vitro investigations. In this report, we present in vitro screening of these candidates and of voriconazole (VCZ) to assess their potential to be substrates and/or inhibitors of UGT2B10. Enzyme kinetics experiments included recombinant UGT2B10 and analytical methods based on ultra high-performance liquid chromatography coupled to mass spectrometry (UHPLC-MS). To determine potential substrates, candidates were incubated at various therapeutically observed concentrations with recombinant UGT2B10 to identify the corresponding glucuronide metabolite. Inhibition capacity was tested using the selective probe cotinine for its glucuronidation to cotinine N-ß-d-glucuronide. IC50 was determined for compounds exhibiting inhibition. Among the tested compounds, LOR (IC50 = 0.01 μM, R2 = 0.9257) and MPA (IC50 = 0.38 mM, R2 = 0.9212) exhibited inhibition potential for UGT2B10. None of the other tested compounds featured inhibition potential and none of the compounds tested exhibited metabolism through UGT2B10. Further exploration on the clinical relevance of this inhibition using modeling strategies, overlapping nature with other UGT isoforms, and screening other molecules for their inhibition potential on UGT2B10 is warranted. UGT1A4 UGT1A6 UGT2B10 Acetaminophen Glucuronidation Hematopoietic stem cell transplantation Lorazepam Mycophenolic acid Sinusoidal obstruction syndrome Voriconazole Glucuronosyltransferase / metabolism Glucuronosyltransferase / antagonists & inhibitors Humans Hematopoietic Stem Cell Transplantation Ligands Mycophenolic Acid / pharmacology Acetaminophen / pharmacology Voriconazole / pharmacology Computer Simulation Child Chromatography, High Pressure Liquid Dewey 615 Dewey 617 Dewey 618 CANSEARCH Foundation OAK Foundation OCAY-17-642 63 Département d'anesthésiologie, pharmacologie, soins intensifs et urgences 229 31 Section des sciences pharmaceutiques 17 58 Département de pédiatrie, gynécologie et obstétrique 223 false 1280 Pharmaco-omiques et médecine de précision 1003 564 Oncologie et hématologie pédiatriques 907 https://yareta.unige.ch/archives/086dd04d-63ae-46b7-b032-9871af429bbd Pharmacology research & perspectives 12 6 1204c518-3e90-4ddd-a2ce-d3ed1cf0055d Article (Published version) Public Article_scientifique_from_europePmc.pdf 1050476 application/pdf CC BY-4.0 048f672314e5f9b49d745c457b683f7cb05dd9a48f6e67908f4c15d4d1db5364 37c0df81-a83f-4f32-8dd1-d4dbbee4db8d Appendix Public PRP2-12-e70011-s001.docx 572137 application/vnd.openxmlformats-officedocument.wordprocessingml.document 7dd25060c3c09dcb94a790d7f6928e4bb6cf1177fbe181a136f258d0455b27a0 openAccess Faculté de médecine / Section de médecine clinique / Département d'anesthésiologie, pharmacologie, soins intensifs et urgences Faculté des sciences / Section des sciences pharmaceutiques Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique

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In vitro screening of UGT2B10 in silico prioritized putative ligands from drugs used in the pediatric hematopoietic stem cell transplantation setting	Pharmacology research & perspectives			2024	101	155

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Gencaslan, Muhammed Yasin