title: Mitochondrial toxicity of selective COX-2 inhibitors via inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria.
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.
authors.affiliation: Section of Analytical Biosciences, Department of Pharmacy, School of Pharmaceutical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: muzeeb.syed@sund.ku.dk.
authors.forename: Muzeeb
authors.initials: M
authors.lastname: Syed
authors.affiliation: Discovery ADME Department, Diabetes Pharmacology and Bioanalysis, Novo Nordisk A/S, Måløv, Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Skonberg
authors.affiliation: Section of Analytical Biosciences, Department of Pharmacy, School of Pharmaceutical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Steen Honoré
authors.initials: SH
authors.lastname: Hansen
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000068579:Celecoxib / Q000633:toxicity; D052246:Cyclooxygenase 2 Inhibitors / Q000633:toxicity*; D004008:Diclofenac / Q000031:analogs & derivatives / Q000633:toxicity; D000077613:Etoricoxib; D007555:Isoxazoles / Q000633:toxicity; D007783:Lactones / Q000633:toxicity; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000633:toxicity; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000633:toxicity; D013450:Sulfones / Q000633:toxicity; D000096926:Benzenesulfonamides
chemical_list: D000255:Adenosine Triphosphate; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors; D004008:Diclofenac; D000077613:Etoricoxib; D007555:Isoxazoles; D007783:Lactones; D011725:Pyridines; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; C406224:valdecoxib; D000096926:Benzenesulfonamides; C473384:lumiracoxib
keywords: ATP; Drug induced liver injury; In vitro metabolism; Oxidative phosphorylation; Rat liver mitochondria; Selective COX-2 inhibitors