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Liver enzyme delayed clearance in rat treated by CSF1 receptor specific antagonist Sotuletinib

Sotuletinib (BLZ945), a CSF1-R specific kinase inhibitor developed for the treatment of Amyotrophic Lateral Sclerosis, induced liver enzyme elevation in absence of hepatocellular lesions in preclinical rat and monkey studies. The monocytic cell family, including Kupffer cells, e.g., the liver-reside...

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Autores principales: Pognan, François, Buono, Chiara, Couttet, Philippe, Galarneau, Jean-René, Timsit, Yoav, Wolf, Armin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9637862/
https://www.ncbi.nlm.nih.gov/pubmed/36353522
http://dx.doi.org/10.1016/j.crtox.2022.100091
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author Pognan, François
Buono, Chiara
Couttet, Philippe
Galarneau, Jean-René
Timsit, Yoav
Wolf, Armin
author_facet Pognan, François
Buono, Chiara
Couttet, Philippe
Galarneau, Jean-René
Timsit, Yoav
Wolf, Armin
author_sort Pognan, François
collection PubMed
description Sotuletinib (BLZ945), a CSF1-R specific kinase inhibitor developed for the treatment of Amyotrophic Lateral Sclerosis, induced liver enzyme elevation in absence of hepatocellular lesions in preclinical rat and monkey studies. The monocytic cell family, including Kupffer cells, e.g., the liver-resident macrophages, are dependent upon CSF1 pathway activation for their survival, proliferation, and differentiation. Kupffer cells act as the main body compartment responsible for elimination of some blood-borne proteins, like ALT, AST, and few others. The depletion of Kupffer cells through CSF1 pathway inhibition has already been hypothesized as responsible for apparent liver enzyme elevation without detectable corresponding liver damage. However, a release of these biomarkers from unseen hepatic lesions or from other organs cannot be excluded. In order to eliminate a potential contribution of ALT elevation from an internal organ source, we injected recombinant his-Tagged ALT1 into rats pretreated with Sotuletinib. The elimination rate of the exogenous ALT1 was significantly lower in treated animals, demonstrating a delayed clearance independently of any potential organ lesions.
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spelling pubmed-96378622022-11-08 Liver enzyme delayed clearance in rat treated by CSF1 receptor specific antagonist Sotuletinib Pognan, François Buono, Chiara Couttet, Philippe Galarneau, Jean-René Timsit, Yoav Wolf, Armin Curr Res Toxicol Article from the special issue Mechanisms of Repro-Tox edited by Terje Svingen Sotuletinib (BLZ945), a CSF1-R specific kinase inhibitor developed for the treatment of Amyotrophic Lateral Sclerosis, induced liver enzyme elevation in absence of hepatocellular lesions in preclinical rat and monkey studies. The monocytic cell family, including Kupffer cells, e.g., the liver-resident macrophages, are dependent upon CSF1 pathway activation for their survival, proliferation, and differentiation. Kupffer cells act as the main body compartment responsible for elimination of some blood-borne proteins, like ALT, AST, and few others. The depletion of Kupffer cells through CSF1 pathway inhibition has already been hypothesized as responsible for apparent liver enzyme elevation without detectable corresponding liver damage. However, a release of these biomarkers from unseen hepatic lesions or from other organs cannot be excluded. In order to eliminate a potential contribution of ALT elevation from an internal organ source, we injected recombinant his-Tagged ALT1 into rats pretreated with Sotuletinib. The elimination rate of the exogenous ALT1 was significantly lower in treated animals, demonstrating a delayed clearance independently of any potential organ lesions. Elsevier 2022-10-29 /pmc/articles/PMC9637862/ /pubmed/36353522 http://dx.doi.org/10.1016/j.crtox.2022.100091 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article from the special issue Mechanisms of Repro-Tox edited by Terje Svingen
Pognan, François
Buono, Chiara
Couttet, Philippe
Galarneau, Jean-René
Timsit, Yoav
Wolf, Armin
Liver enzyme delayed clearance in rat treated by CSF1 receptor specific antagonist Sotuletinib
title Liver enzyme delayed clearance in rat treated by CSF1 receptor specific antagonist Sotuletinib
title_full Liver enzyme delayed clearance in rat treated by CSF1 receptor specific antagonist Sotuletinib
title_fullStr Liver enzyme delayed clearance in rat treated by CSF1 receptor specific antagonist Sotuletinib
title_full_unstemmed Liver enzyme delayed clearance in rat treated by CSF1 receptor specific antagonist Sotuletinib
title_short Liver enzyme delayed clearance in rat treated by CSF1 receptor specific antagonist Sotuletinib
title_sort liver enzyme delayed clearance in rat treated by csf1 receptor specific antagonist sotuletinib
topic Article from the special issue Mechanisms of Repro-Tox edited by Terje Svingen
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9637862/
https://www.ncbi.nlm.nih.gov/pubmed/36353522
http://dx.doi.org/10.1016/j.crtox.2022.100091
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