Comparative Antioxidant Effects of Allopurinol and Febuxostat in Doxorubicin-Treated Rats

Abstract

Background and objectives: Doxorubicin (DOX) suffers from the limitation of oxidative and nitrosative stress-derived cardiac toxicity during clinical use. Allopurinol, febuxostat, and other xanthine oxidase inhibitors are antioxidants that may mitigate oxidative injury caused by DOX. The objective of this study was to compare the effects of allopurinol and febuxostat on the biomarkers of oxidative stress and nitrosative stress in a rat model for doxorubicin-induced oxidative damage.

Methods: Forty adult rats were randomly allocated to four groups (n = 10/group): Control, doxorubicin-treated (D), doxorubicin + allopurinol-treated (A), and doxorubicin + febuxostat-treated (F). Doxorubicin was used to induce oxidative stress, and allopurinol and febuxostat were given in combination as protectors. Serum concentrations of malondialdehyde (MDA), nitric oxide (NO), 3-nitrotyrosine (3-NT), and total antioxidant status (TAS) were determined by ELISA-based assays. Histopathological examination of the aorta was also performed. Data were analyzed statistically using ANOVA with appropriate post hoc testing at p < 0.05 significance.

Results: Doxorubicin administration significantly increased serum MDA, TAS, NO, and 3-NT concentrations and caused marked histopathological damage in aortic tissues. The elevation of NO in the doxorubicin group may represent a compensatory response to oxidative stress aimed at maintaining vascular homeostasis, as nitric oxide normally functions as an important endogenous vasodilator and antioxidant. Both allopurinol and febuxostat significantly reduced MDA levels compared with the doxorubicin group. Allopurinol also significantly decreased NO concentrations, whereas febuxostat had no significant effect. Neither treatment significantly improved TAS or 3-NT concentrations. Histopathological examination demonstrated attenuation of doxorubicin-induced cardiovascular injury by both drugs, with febuxostat exhibiting superior preservation of aortic architecture.

Conclusion: Both allopurinol and febuxostat exerted protective effects against doxorubicin-induced oxidative stress, primarily by reducing lipid peroxidation. Allopurinol additionally decreased nitric oxide concentrations. Despite limited differences in circulating biomarkers, febuxostat provided superior histopathological protection.