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Nephro- and Cardiotoxic Effects of Etoricoxib: Insights into Arachidonic Acid Metabolism and Beta-Adrenergic Receptor
Yahya F Jamous1, Badrah S Alghamdi2,3, Yazun Jarrar4
1Vaccines and Bioprocessing National Center, King Abdulaziz City for Science and Technology (KACST), Riyadh 12354, Saudi Arabia.
Abstract:
Background: Etoricoxib is a widely used anti-inflammatory drug, but its safety profile concerning cardiovascular and renal health remains inadequately explored. This study aimed to assess the nephro- and cardiotoxic effects of etoricoxib in a murine model, with a focus on its impact on arachidonic acid-metabolizing enzymes and beta-adrenergic receptors associated with drug-induced toxicity. Methods: Thirty-five BALB/C mice were randomly assigned to five groups: control, low-dose etoricoxib, high-dose etoricoxib, low-dose celecoxib, and high-dose celecoxib (a well-known nephro- and cardiotoxic NSAID). The treatments were administered for 28 days, after which hearts and kidneys were excised for physical and histopathological analysis, and the expression of arachidonic acid-metabolizing enzymes (cytochrome P450s, lipoxygenases, cyclooxygenases) and beta-1 adrenergic receptor (adrb1) and angiotensin-converting enzyme (ace2) genes were quantified using quantitative reverse transcription PCR (qRT-PCR). Results: Etoricoxib administration resulted in dose-dependent nephro- and cardiotoxic effects. Renal histology revealed glomerular atrophy or hypertrophy and significant damage to the proximal and distal convoluted tubules, including epithelial flattening, cytoplasmic vacuolation, and luminal widening. Cardiac analysis showed disorganized muscle fibers and hyaline degeneration. These changes were associated with altered gene expression: the downregulation of cox2, cyp1a1, and cyp2c29 in the kidneys and the upregulation of cyp4a12, cox2, and adrb1, along with the downregulation of cyp2c29 and ace2 in the heart. Conclusions: Etoricoxib induces nephro- and cardiotoxicity, marked by alterations in arachidonic acid metabolism and beta-adrenergic signaling pathways. The drug affects the expression of arachidonic acid-metabolizing enzymes and adrb1 in the heart while downregulating cox2 and other related enzymes in the kidneys. These findings underscore the need for caution when prescribing etoricoxib, particularly in patients with pre-existing renal or cardiac conditions.
Insights
Etoricoxib causes dose-dependent kidney and heart damage in mice by altering arachidonic acid metabolism and beta-adrenergic signaling. Caution is advised, especially for patients with pre-existing cardiac or renal conditions.
Area of Science:
- Pharmacology
- Toxicology
- Molecular Biology
Background:
- Etoricoxib is a common anti-inflammatory drug with an incompletely understood safety profile regarding cardiovascular and renal health.
- Investigating etoricoxib's effects on arachidonic acid metabolism and beta-adrenergic receptors is crucial for understanding its toxicity.
Purpose of the Study:
- To assess the nephrotoxic and cardiotoxic effects of etoricoxib in a murine model.
- To examine the impact of etoricoxib on key enzymes involved in arachidonic acid metabolism and specific signaling pathways.
Main Methods:
- BALB/C mice were divided into five groups, receiving etoricoxib, celecoxib, or a control for 28 days.
- Kidneys and hearts were analyzed histopathologically, and gene expression of relevant enzymes and receptors was quantified using qRT-PCR.
Main Results:
- Etoricoxib induced dose-dependent nephrotoxicity (glomerular changes, tubular damage) and cardiotoxicity (disorganized fibers, hyaline degeneration).
- Significant alterations in gene expression were observed, including downregulation of COX-2 and CYP enzymes in kidneys and upregulation of ADRB1 and CYP4A12 in the heart.
Conclusions:
- Etoricoxib exerts nephro- and cardiotoxic effects mediated by changes in arachidonic acid metabolism and beta-adrenergic signaling.
- The study highlights the need for careful consideration of etoricoxib use in patients with compromised renal or cardiac function.
