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NSAIDs Nonselective/semiselective | Sources of ROS generation | Cells/models/animals studied | Outcomes | References |
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Diclofenac, indomethacin, ketoprofen | Mitochondrial respiration | Saccharomyces cerevisiae Yeast cells BY4741 and mitochondrial DNA deletion (rho0) strains | These NSAIDs target mitochondria to induce cell toxicity | [95] |
Ibuprofen and naproxen | These NSAIDS induce toxicity independent of mitochondrial respiration | [95] |
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Indomethacin, sodium diclofenac, flurbiprofen, zaltoprofen, and mofezolac | ND | Human gastric epithelial cell line AGS | All NSAIDs except mofezolac increased apoptotic DNA fragmentation and expression of COX-2 mRNA. DNA fragmentation induced by indomethacin or flurbiprofen was reduced by antioxidants. Indomethacin at 1 mM was a potent inducer of ROS generation in the cells | [79] |
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Diclofenac and naproxen | NADPH oxidases | Spontaneous hypertensive rats | NADPH oxidase expression increased in the heart and aorta by diclofenac and naproxen. ROS levels increased due to NADPH oxidase | [114] |
Human EA.hy 926 Endothelial cells | Nox2 isoform of NADPH oxidase is increased by diclofenac | [114] |
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Aspirin, naproxen, and piroxicam | NADPH oxidases | Rat adipocytes | Activation of NOX 4 isoform of NADPH oxidase results in the generation of H2O2 | [115] |
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Indomethacin | Xanthine oxidases | Human colonic adenocarcinoma cells (Caco-2 cells) | Xanthine oxidase activity increases by more than 100% 1 hour after treatment | [96] |
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Indomethacin | Mitochondria superoxide leakage | Rat gastric epithelial cell line RGM1 | Indomethacin induced the leakage of superoxide anion in the isolated mitochondria from the gastric RGM1 cells | [93] |
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Indomethacin, diclofenac sodium, and aspirin | ND | Rat gastric epithelial cell line RGM1 and rat small intestinal epithelial cell line IEC6 | Indomethacin, diclofenac, and aspirin in gastric RGM1 cells and small intestinal IEC6 cells increased lipid peroxidation | [93] |
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Sulindac, sulindac sulfide, and sulindac sulfone | ND | Pancreas carcinoma BXPC3, glioblastoma A172, colon carcinoma DLD-1, oral squamous SAS, and acute myelocytic leukemia HL60 cells | The NSAID sulindac and its metabolites sulindac sulfide and sulindac sulfone all increased ROS generation. Sulindac sulfide showed the greatest ROS generation | [80] |
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Indomethacin, piroxicam, and aspirin | Lipoxygenases | Gastric and intestinal mucosa in mice | Results in an overproduction of leukotrienes and products of 5-lipoxygenase activity. Increases in leukotriene and 5-lipoxygenase activity have been associated with ROS generation | [123, 124, 127] |
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Indomethacin | Lipoxygenases | Efferent gastric circulation of pigs | Time dependent formation of leukotriene-C4 | [128] |
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Diclofenac | Cytochrome P450 enzymes | Saccharomyces cerevisiae yeast cells expressing the mutant P 450 BM3 M11 (capable of metabolizing diclofenac similar to humans) | Increased ROS production by ~1.5 and 1.8 times at concentrations of 30 μM and 50 μM, respectively, compared to wild type | [140] |
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Diclofenac, indomethacin, ketoprofen, and naproxen | Cytochrome P450 enzymes | Saccharomyces cerevisiae Yeast cells BY4741 and mitochondrial DNA deletion (rho0) strains | NSAIDs metabolism associated with increased P450-related toxicity | [95] |
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