ABSTRACT
AIMS: Consumption of nutraceuticals without enough data regarding their interactions has raised safety concerns. Importantly, consumption of some natural-products in health-compromised conditions has caused liver injury due to the evolved pro-oxidant load. This study evaluates the safety of quercetin (QUR), as an extensively-used flavonoid owing to its antioxidant and hepatoprotective activities, in normal- and lipopolysaccharides (LPS)-primed livers, and to investigate the influence of the LPS-induced mild inflammatory/febrile condition on QUR effects. MAIN METHODS: For liver priming, a non-injurious LPS dose that mediates limited inflammation/mild fever was chosen. Selection of QUR dose/duration of treatment, for a coherent combination-regimen, was also adopted. Single LPS i.p injection (1.5 mg/kg)/oral QUR (20 mg/kg/day, IG) for 5-days was the optimal regimen for the combination group. On day-6, serum ALT/AST/ALP levels were measured, as liver-damage biomarkers. Hepatic; MDA/GSH were determined, as oxidative-stress measures, Bcl-2/cleaved-caspase-3 were assessed as apoptosis biomarkers, IL-6 expression/NF-κB/Nrf-2 immunoreactivities were evaluated as regulators for inflammation. KEY FINDINGS: Exaggerated hepatic injury was seen upon QUR treatment in LPS-presensitized mice; as evidenced by liver histopathological degeneration, which was confirmed by biochemical elevations of serum AST/ALT/ALP, along with oxidant-burden increase (↑MDA/↓GSH) and molecular augmentation of inflammation (NF-κB/IL-6 activation) that led to enhancement of proapoptotic signaling (caspase-3 activation/Bcl-2 inhibition). Such events were accompanied by potentiation of endogenous anti-inflammatory/antioxidant response (↑ hepatic Nrf-2). SIGNIFICANCE: The study highlights caution when QUR is consumed in health-compromised conditions, by revealing the role of fever/mild inflammation in enhancing liver toxicity upon QUR utilization, which was not apparent with moderate consumption of QUR-alone.
