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Differential hepatoprotective mechanisms of rutin and quercetin in carbon tetrachloride-intoxicated BALB/cN mice

The aim of this study was to investigate the hepatoprotective mechanisms of flavonoid rutin against carbon tetrachloride CCl4-induced liver damage in mice and compare it with its aglycone quercetin. Rutin at doses of 10, 50, and 150 mg/kg and quercetin at 50 mg/kg were administered intraperitoneally into BALB/cN mice once daily for 5 consecutive days before administration of CCl4. The animals were sacrificed 24 h later. CCl4-intoxication increased the activity of plasma transaminases and induced severe liver necrosis. In addition, the hepatic activity of Cu/Zn superoxide dismutase (Cu/Zn SOD) and glutathione (GSH) levels were reduced, whereas nitrotyrosine (3-NT) formation increased. Pretreatment with rutin, and to the less extent, quercetin, significantly reduced the activity of plasma transaminases and improved histological signs of acute liver damage. Quercetin prevented the decrease in Cu/Zn SOD activity more potently than rutin, however, it was less effective in the suppression of 3-NT formation. Quercetin, and to the less extent, rutin, significantly attenuated inflammation in the liver by down-regulating CCl4-induced activation of nuclear factor kappaB (NF-κB), tumor necrosis factor-alpha (TNF-α), and cyclooxygenase (COX-2). The expression of inducible nitric oxide synthase (iNOS) was more potently suppressed by rutin than quercetin. Treatment with both flavonoids significantly increased NF-E2-related factor 2 (Nrf2) and heme oxygenase (HO-1) expression in injured livers, although quercetin was less effective than rutin at the equivalent dose. The results of this study suggest that rutin provides stronger protection against hepatocellular damage and nitrosative stress but has weaker antioxidant and anti-inflammatory activity than quercetin.

hepatotoxicity; rutin; quercetin; nuclear factor-kappa B; tumor necrosis factor-alpha; cyclooxygenase-2; nitric oxide synthase; NF-E2-related factor 2; heme oxygenase-1; transforming growth factor-beta 1

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