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Mitochondrial toxicity of selective COX-2 inhibitors via inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria.
- Source :
-
Toxicology in vitro : an international journal published in association with BIBRA [Toxicol In Vitro] 2016 Apr; Vol. 32, pp. 26-40. Date of Electronic Publication: 2015 Dec 09. - Publication Year :
- 2016
-
Abstract
- Cyclooxygenase-2 (COX-2) inhibitors (coxibs) are non-steroidal anti-inflammatory drugs (NSAIDs) designed to selectively inhibit COX-2. However, drugs of this therapeutic class are associated with drug induced liver injury (DILI) and mitochondrial injury is likely to play a role. The effects of selective COX-2 inhibitors on inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria were investigated. The order of potency of inhibition of ATP synthesis was: lumiracoxib (IC50: 6.48 ± 2.74 μM)>celecoxib (IC50: 14.92 ± 6.40 μM)>valdecoxib (IC50: 161.4 ± 28.6 μM)>rofecoxib (IC50: 238.4 ± 79.2 μM)>etoricoxib (IC50: 405.1 ± 116.3 μM). Mechanism based inhibition of ATP synthesis (Kinact 0.078 min(-1) and KI 21.46 μM and Kinact/KI ratio 0.0036 min(-1)μM(-1)) was shown by lumiracoxib and data suggest that the opening of the MPT pore may not be the mechanism of toxicity. A positive correlation (with r(2)=0.921) was observed between the potency of inhibition of ATP synthesis and the log P values. The in vitro metabolism of coxibs in rat liver mitochondria yielded for each drug substance a major single metabolite and identified a hydroxy metabolite with each of the coxibs and these metabolites did not alter the inhibition profile of ATP synthesis of the parent compound. The results suggest that coxibs themselves could be involved in the hepatotoxic action through inhibition of ATP synthesis.<br /> (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Celecoxib toxicity
Diclofenac analogs & derivatives
Diclofenac toxicity
Etoricoxib
Isoxazoles toxicity
Lactones toxicity
Male
Mitochondria, Liver metabolism
Oxidative Phosphorylation drug effects
Pyridines toxicity
Rats, Sprague-Dawley
Sulfonamides toxicity
Sulfones toxicity
Adenosine Triphosphate metabolism
Cyclooxygenase 2 Inhibitors toxicity
Mitochondria, Liver drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1879-3177
- Volume :
- 32
- Database :
- MEDLINE
- Journal :
- Toxicology in vitro : an international journal published in association with BIBRA
- Publication Type :
- Academic Journal
- Accession number :
- 26689325
- Full Text :
- https://doi.org/10.1016/j.tiv.2015.12.003