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Nonsteroidal antiinflammatory drugs and uncoupling of mitochondrial oxidative phosphorylation
Objective:
There is a lack of correlation between cyclooxygenase (COX) inhibition and nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) damage; it has been suggested that mucosal damage may be initiated by a "topical" action of NSAIDs involving mitochondrial injury. We evaluated the effect of a range of NSAIDs and related compounds on mitochondrial function and assessed the differences between them in relation to their physicochemical properties.
Methods:
Stimulation of respiration, as an indicator of mitochondrial uncoupling, was measured in isolated coupled rat liver mitochondrial preparations, using an oxygen electrode.
Results:
Conventional NSAIDs and acidic prodrugs all had stimulatory effects on mitochondrial respiration at micromolar concentrations (0.02-2.7 microM); higher concentrations were inhibitory. The uncoupling potency was inversely correlated with drug pKa (r = -0.87, P < 0.001; n = 12). Drugs known to have good GI tolerability, including modified flurbiprofen (dimero-flurbiprofen and nitrobutyl-flurbiprofen), nabumetone (a non-acidic prodrug), and non-acidic highly selective COX-2 inhibitors, did not cause uncoupling.
Conclusion:
The ability to uncouple mitochondrial oxidative phosphorylation is a common characteristic of antiinflammatory agents with an ionizable group. Modification or absence of an ionizable moiety reduces the effect on mitochondria and could lead to improved NSAID GI safety.
Insights
Nonsteroidal anti-inflammatory drugs (NSAIDs) can damage the stomach lining by affecting mitochondria. Modifying NSAIDs to lack an ionizable group may improve gastrointestinal safety.
Area of Science:
- Biochemistry
- Pharmacology
- Toxicology
Background:
- Nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) damage lacks correlation with cyclooxygenase (COX) inhibition.
- Mucosal damage may stem from a "topical" action of NSAIDs, specifically mitochondrial injury.
Purpose of the Study:
- Evaluate the impact of various NSAIDs and related compounds on mitochondrial function.
- Correlate these effects with the physicochemical properties of the drugs.
Main Methods:
- Measured stimulation of respiration in isolated rat liver mitochondria using an oxygen electrode as an indicator of mitochondrial uncoupling.
- Assessed a range of NSAIDs and related compounds.
Main Results:
- Conventional NSAIDs and acidic prodrugs stimulated mitochondrial respiration at micromolar concentrations, with higher concentrations being inhibitory.
- Uncoupling potency showed an inverse correlation with drug pKa (r = -0.87).
- NSAIDs with good GI tolerability (e.g., modified flurbiprofen, nabumetone, non-acidic COX-2 inhibitors) did not cause uncoupling.
Conclusions:
- The uncoupling of mitochondrial oxidative phosphorylation is a shared trait among anti-inflammatory agents possessing an ionizable group.
- Reducing or eliminating the ionizable moiety may decrease mitochondrial effects and enhance NSAID GI safety.