RESUMEN
AIM: Intrahepatic cholestasis is a common pathological condition of several types of liver disorders. In this study, we aimed to investigate the regulatory effects of quercetin (QU) on selected phosphodiesterase inhibitors against alpha-naphthyl isothiocyanate (ANIT)-induced acute intrahepatic cholestasis. METHODS: Cholestasis was induced in Wistar albino rats by ANIT as a single dose (60 mg/kg; P·O.). QU (50 mg/kg, daily, P·O.), sildenafil (Sild; 10 mg/kg, twice daily, P·O.), and pentoxifylline (PTX; 50 mg/kg, daily, P.O.) were evaluated either alone or in combinations for 10 days for their antioxidant, anti-inflammatory, and anti-pyroptotic effects. RESULTS: ANIT produced a prominent intrahepatic cholestasis as evidenced by a significant alteration in liver functions, histological structure, inflammatory response, and oxidative stress biomarkers. Furthermore, up-regulation of NF-κB-p65, TLR4, NLRP3, cleaved caspase-1, IKK-ß, and IL-1ß concurrently with down-regulation of Nrf-2, HO-1, and PPAR-γ expressions were observed after ANIT. QU, Sild, or PTX treatment significantly alleviated the disturbance induced by ANIT. These findings were further supported by the improvement in histopathological features. Additionally, co-administration of QU with Sild or PTX significantly improved liver defects due to ANIT as compared to the individual drugs. SIGNIFICANCE: Combined QU with Sild or PTX exhibited promising hepatoprotective effects and anti-cholestatic properties through modulation of Nrf2/ARE, TLR4/NF- κB, and NLRP3/IL-1ß signaling pathways.