Biological Role of Pazopanib and Sunitinib Aldehyde Derivatives in Drug-Induced Liver Injury
Maud Maillard,
Cécile Arellano,
Christelle Vachoux,
Christine Chevreau,
Nicolas J. Cabaton,
Frédéric Pont,
Nathalie Saint-Laurent,
Thierry Lafont,
Etienne Chatelut,
Fabienne Thomas
Affiliations
Maud Maillard
Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm, Université Toulouse III-Paul Sabatier, 2 Avenue Hubert Curien, CS53717, CEDEX 1, 31037 Toulouse, France
Cécile Arellano
Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm, Université Toulouse III-Paul Sabatier, 2 Avenue Hubert Curien, CS53717, CEDEX 1, 31037 Toulouse, France
Christelle Vachoux
Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm, Université Toulouse III-Paul Sabatier, 2 Avenue Hubert Curien, CS53717, CEDEX 1, 31037 Toulouse, France
Christine Chevreau
Institut Claudius Regaud IUCT-Oncopole, CEDEX 9, 31059 Toulouse, France
Nicolas J. Cabaton
Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France
Frédéric Pont
Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm, Université Toulouse III-Paul Sabatier, 2 Avenue Hubert Curien, CS53717, CEDEX 1, 31037 Toulouse, France
Nathalie Saint-Laurent
Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm, Université Toulouse III-Paul Sabatier, 2 Avenue Hubert Curien, CS53717, CEDEX 1, 31037 Toulouse, France
Thierry Lafont
Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm, Université Toulouse III-Paul Sabatier, 2 Avenue Hubert Curien, CS53717, CEDEX 1, 31037 Toulouse, France
Etienne Chatelut
Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm, Université Toulouse III-Paul Sabatier, 2 Avenue Hubert Curien, CS53717, CEDEX 1, 31037 Toulouse, France
Fabienne Thomas
Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm, Université Toulouse III-Paul Sabatier, 2 Avenue Hubert Curien, CS53717, CEDEX 1, 31037 Toulouse, France
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.
