Differential toxic effects of azathioprine, 6-mercaptopurine and 6-thioguanine on human hepatocytes

Autor: Fabrice Morel, Christophe Nicolas-Nicolaz, Elise Petit, Hanane Akhdar, Sophie Langouët, André Guillouzo
Přispěvatelé: Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Détoxication et réparation tissulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Rok vydání: 2007
Předmět:
Antioxidant
MESH: IMP Dehydrogenase
Hepatoma cells
medicine.medical_treatment
MESH: Flow Cytometry
Azathioprine
Pharmacology
Toxicology
MESH: Hepatocytes
0302 clinical medicine
Adenosine Triphosphate
IMP Dehydrogenase
IMP dehydrogenase
MESH: Reverse Transcriptase Polymerase Chain Reaction
MESH: Adenosine Triphosphate
RNA
Neoplasm
MESH: Antimetabolites
Antineoplastic
0303 health sciences
biology
Thiopurine methyltransferase
Mercaptopurine
Reverse Transcriptase Polymerase Chain Reaction
MESH: Thioguanine
MESH: Reactive Oxygen Species
Immunosuppression
General Medicine
Flow Cytometry
3. Good health
[SDV.TOX]Life Sciences [q-bio]/Toxicology
030220 oncology & carcinogenesis
HepaRG
MESH: 6-Mercaptopurine
Human
medicine.drug
Antimetabolites
Antineoplastic
03 medical and health sciences
medicine
Humans
Enzyme inducer
Thioguanine
MESH: Azathioprine
030304 developmental biology
MESH: Humans
Toxicity
Thiopurine
Metabolism
MESH: RNA
Neoplasm
biology.protein
Hepatocytes
Reactive Oxygen Species
Zdroj: Toxicology in Vitro
Toxicology in Vitro, Elsevier, 2008, 22 (3), pp.632-42. ⟨10.1016/j.tiv.2007.12.004⟩
Toxicology in Vitro, 2008, 22 (3), pp.632-42. ⟨10.1016/j.tiv.2007.12.004⟩
ISSN: 0887-2333
DOI: 10.1016/j.tiv.2007.12.004⟩
Popis: International audience; Thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) are therapeutic compounds widely administered in the clinic for their multiple uses (autoimmune diseases, post-transplant immunosuppression and cancer). Despite these advantages, their therapeutic potential is limited by occasional adverse effects (myelotoxicity and hepatotoxicity) and by a relatively frequent lack of efficacy. Previous studies have demonstrated that azathioprine decreased the viability of rat hepatocytes. In order to investigate cytotoxic effects of thiopurines in human liver, we used primary human hepatocytes and a highly differentiated human hepatoma cell line, HepaRG, treated or not with azathioprine, 6-mercaptopurine and 6-thioguanine. In parallel, expression of the genes involved in the metabolism of thiopurines, glutathione synthesis and antioxidant defences was measured by quantitative PCR. We clearly demonstrate that human liver parenchymal cells were much less sensitive than rat hepatocytes to thiopurine treatments. The toxic effects appeared after 96 h of treatment while ATP depletion was observed after a 24 h incubation with azathioprine and 6-mercaptopurine. Toxic effects were more pronounced for azathioprine and 6-mercaptopurine, when compared to 6-thioguanine, and might explain glutathione synthesis and antioxidant enzyme induction only by these two drugs. Finally, we also demonstrate for the first time an up-regulation by azathioprine and 6-mercaptopurine of inosine monophosphate dehydrogenase which might have consequences on the de novo biosynthesis of guanine nucleotides and thiopurines metabolism.
Databáze: OpenAIRE
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