Mitochondrial toxicity of diclofenac and its metabolites via inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria: Possible role in drug induced liver injury (DILI)
| Autor: | Christian Skonberg, Muzeeb Syed, Steen Honoré Hansen |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Diclofenac Metabolite Mitochondria Liver Oxidative phosphorylation Pharmacology Mitochondrion Toxicology Oxidative Phosphorylation Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Adenosine Triphosphate 0302 clinical medicine hemic and lymphatic diseases medicine Animals Liver injury ATP synthase biology Anti-Inflammatory Agents Non-Steroidal General Medicine Glutathione medicine.disease stomatognathic diseases Mitochondrial toxicity 030104 developmental biology chemistry Biochemistry 030220 oncology & carcinogenesis biology.protein Chemical and Drug Induced Liver Injury circulatory and respiratory physiology medicine.drug |
| Zdroj: | Toxicology in Vitro. 31:93-102 |
| ISSN: | 0887-2333 |
| DOI: | 10.1016/j.tiv.2015.11.020 |
| Popis: | Diclofenac is a widely prescribed NSAID, which by itself and its reactive metabolites (Phase-I and Phase-II) may be involved in serious idiosyncratic hepatotoxicity. Mitochondrial injury is one of the mechanisms of drug induced liver injury (DILI). In the present work, an investigation of the inhibitory effects of diclofenac (Dic) and its phase I [4-hydroxy diclofenac (4'-OH-Dic) and 5-hydroxy diclofenac (5-OH-dic)] and Phase-II [diclofenac acyl glucuronide (DicGluA) and diclofenac glutathione thioester (DicSG)] metabolites, on ATP synthesis in rat liver mitochondria was carried out. A mechanism based inhibition of ATP synthesis is exerted by diclofenac and its metabolites. Phase-I metabolite (4'-OH-Dic) and Phase-II metabolites (DicGluA and DicSG) showed potent inhibition (2-5 fold) of ATP synthesis, where as 5-OH-Dic, one of the Phase-I metabolite, was a less potent inhibitor as compared to Dic. The calculated kinetic constants of mechanism based inhibition of ATP synthesis by Dic showed maximal rate of inactivation (Kinact) of 2.64 ± 0.15 min(-1) and half maximal rate of inactivation (KI) of 7.69 ± 2.48 μM with Kinact/KI ratio of 0.343 min(-1) μM(-1). Co-incubation of mitochondria with Dic and reduced GSH exhibited a protective effect on Dic mediated inhibition of ATP synthesis. Our data from this study strongly indicate that Dic as well as its metabolites could be involved in the hepato-toxic action through inhibition of ATP synthesis. |
| Databáze: | OpenAIRE |
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