Biological Role of Pazopanib and Sunitinib Aldehyde Derivatives in Drug-Induced Liver Injury

Autor: Maud Maillard, Cécile Arellano, Christelle Vachoux, Christine Chevreau, Nicolas J. Cabaton, Frédéric Pont, Nathalie Saint-Laurent, Thierry Lafont, Etienne Chatelut, Fabienne Thomas
Přispěvatelé: Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), The clinical part of the study (plasma analysis in patients) was funded by a PHRCi grant from GIRCI-SOHO (Groupements Interrégionaux de Recherche Clinique et d’Innovation Sud Ouest Outre Mer Hospitaliers) (Study reference: EUDRACT 2015-001051-68)., LESUR, Hélène
Rok vydání: 2022
Předmět:
Zdroj: Metabolites
Metabolites, 2022, 12 (9), pp.852. ⟨10.3390/metabo12090852⟩
Metabolites; Volume 12; Issue 9; Pages: 852
ISSN: 2218-1989
DOI: 10.3390/metabo12090852⟩
Popis: International audience; Tyrosine kinase inhibitors pazopanib and sunitinib are both used to treat advanced renal cell carcinoma but expose patients to an increased risk of hepatotoxicity. We have previously identified two aldehyde derivatives for pazopanib and sunitinib (P-CHO and S-CHO, respectively) in liver microsomes. In this study, we aimed to decipher their role in hepatotoxicity by treating HepG2 and HepaRG hepatic cell lines with these derivatives and evaluating cell viability, mitochondrial dysfunction, and oxidative stress accumulation. Additionally, plasma concentrations of P-CHO were assessed in a cohort of patients treated with pazopanib. Results showed that S-CHO slightly decreased the viability of HepG2, but to a lesser extent than sunitinib, and affected the maximal respiratory capacity of the mitochondrial chain. P-CHO decreased viability and ATP production in HepG2. Traces of P-CHO were detected in the plasma of patients treated with pazopanib. Overall, these results showed that P-CHO and S-CHO affect hepatocyte integrity and could be involved in the pazopanib and sunitinib hepatotoxicity.
Databáze: OpenAIRE
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