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

Aim: To investigate the hepatoprotective mechanisms of flavonoid rutin against carbon tetrachloride (CCl4)-induced liver damage in mice and compare it with its aglycone quercetin. Methods: 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 intraperitoneal injection of CCl4. The animals were sacrificed 24 h later. Results: Pretreatment with rutin, and to the less extent, quercetin, significantly reduced the activity of plasma transaminases and improved histological signs of acute liver damage in CCl4- intoxicated mice. Quercetin prevented the decrease in Cu/Zn superoxide dismutase (SOD) activity in CCl4-intoxicated mice more potently than rutin, however, it was less effective in the suppression of nitrotyrosine (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. In contrast, transforming growth factor-beta1 (TGF- β1) expression was more suppressed by quercetin. Conclusions: Rutin provided stronger protection against nitrosative stress and hepatocellular damage but had weaker antioxidant and anti- inflammatory activity and antifibrotic potential than quercetin, which could be attributed to the presence of rutinoside moiety in position 3 of the C ring.

hepatotoxicity; rutin; quercetin; nuclear factor-kappaB; tumor necrosis factor-alpha; cyclooxygenase-2; nitric oxide synthase; NF-E2-related factor 2; heme oxygenase-1; transforming growth factor-beta1

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