Metabolomic Response to Non-Steroidal Anti-Inflammatory Drugs.
1University of Pennsylvania.
Research Square
|December 23, 2024
Summary
Naproxen, a common pain reliever, lowers tryptophan levels by displacing it, not by inhibiting Cox enzymes. Restoring tryptophan levels in mice reduced naproxen-induced gut damage and heart inflammation.
Area of Science:
- Biochemistry
- Pharmacology
- Immunology
Background:
- Non-steroidal anti-inflammatory drugs (NSAIDs) alleviate pain and inflammation but cause gastrointestinal and cardiovascular side effects.
- Traditional NSAIDs and selective cyclooxygenase-2 (COX-2) inhibitors like celecoxib have different safety profiles.
- The precise mechanisms underlying NSAID-induced side effects are not fully understood.
Purpose of the Study:
- To compare the effects of naproxen and celecoxib in humans and mice.
- To investigate the impact of naproxen on tryptophan and kynurenine levels.
- To elucidate the mechanism of naproxen-induced tryptophan depression and its role in side effects.
Main Methods:
- Human volunteers were treated with naproxen, and plasma levels of tryptophan and kynurenine were measured.
- Experiments were replicated in mice to validate human findings.
- Studies in mice explored the role of COX-1 and COX-2 inhibition versus tryptophan displacement.
- Tryptophan supplementation was used in mice to assess its effect on naproxen-induced side effects.
Main Results:
- Naproxen treatment led to decreased plasma tryptophan and kynurenine levels in humans and mice.
- Tryptophan depression was attributed to naproxen displacing bound tryptophan, independent of COX-1 or COX-2 inhibition.
- Tryptophan supplementation in mice mitigated naproxen-induced fecal blood loss.
- Restoring tryptophan levels also reduced IL-1β-driven inflammatory gene expression in the heart.
Conclusions:
- Naproxen's mechanism for reducing tryptophan levels involves displacement, not COX inhibition.
- This tryptophan depletion may contribute to NSAID-related gastrointestinal and cardiovascular adverse effects.
- Tryptophan supplementation shows potential as a therapeutic strategy to counteract naproxen's side effects.
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