Investigating dihydroorotate dehydrogenase inhibitor mediated mitochondrial dysfunction in hepatic in vitro models

التفاصيل البيبلوغرافية
العنوان: Investigating dihydroorotate dehydrogenase inhibitor mediated mitochondrial dysfunction in hepatic in vitro models
المؤلفون: Neil French, Amy E. Chadwick, Samantha W. Jones, B. Kevin Park, Sophie L. Penman
المصدر: Toxicology in Vitro
سنة النشر: 2020
مصطلحات موضوعية: 0301 basic medicine, Oxidoreductases Acting on CH-CH Group Donors, Toluidines, Cell Respiration, Dihydroorotate Dehydrogenase, Hydroxybutyrates, Antineoplastic Agents, Mitochondrion, Pharmacology, Toxicology, Models, Biological, Salicylanilides, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Adenosine Triphosphate, In vivo, Teriflunomide, Nitriles, medicine, Humans, Dicarboxylic Acids, Dihydroorotate Dehydrogenase Inhibitor, Leflunomide, Biphenyl Compounds, General Medicine, Triazoles, Mitochondria, 030104 developmental biology, chemistry, Liver, 030220 oncology & carcinogenesis, Crotonates, Pyrimidine metabolism, Dihydroorotate dehydrogenase, Drug metabolism, Immunosuppressive Agents, medicine.drug
الوصف: Inhibition of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzymatic step in de novo pyrimidine synthesis, has broad immunosuppressive effects in vivo and shows promise as a therapeutic target for the treatment of malignancies, viral infections and auto-immune diseases. Whilst there are numerous DHODH inhibitors under development, leflunomide and teriflunomide are the only FDA approved compounds on the market, each of which have been issued with black-box warnings for hepatotoxicity. Mitochondrial dysfunction is a putative mechanism by which teriflunomide and leflunomide elicit their hepatotoxic effects, however it is as yet unclear whether this is shared by other nascent DHODH inhibitors. The present study aimed to evaluate the propensity for DHODH inhibitors to mediate mitochondrial dysfunction in two hepatic in vitro models. Initial comparisons of cytotoxicity and ATP content in HepaRG® cells primed for oxidative metabolism, in tandem with mechanistic evaluations by extracellular flux analysis identified multifactorial toxicity and moderate indications of respiratory chain dysfunction or uncoupling. Further investigations using HepG2 cells, a hepatic line with limited capability for phase I xenobiotic metabolism, identified leflunomide and brequinar as positive mitochondrial toxicants. Taken together, biotransformation of some DHODH inhibitor species may play a role in mediating or masking hepatic mitochondrial liabilities.
وصف الملف: application/pdf
تدمد: 1879-3177
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::975bd15398202d0681c18886c02f9b01
https://pubmed.ncbi.nlm.nih.gov/33460737
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....975bd15398202d0681c18886c02f9b01
قاعدة البيانات: OpenAIRE