Differential hepatoprotective mechanisms of rutin and quercetin in CCl(4)-intoxicated BALB/cN mice.
OBJECTIVE
To investigate the mechanisms underlying the protective effects of quercetin-rutinoside (rutin) and its aglycone quercetin against CCl(4)-induced liver damage in mice.


METHODS
BALB/cN mice were intraperitoneally administered rutin (10, 50, and 150 mg/kg) or quercetin (50 mg/kg) once daily for 5 consecutive days, followed by the intraperitoneal injection of CCl(4) in olive oil (2 mL/kg, 10% v/v). The animals were sacrificed 24 h later. Blood was collected for measuring the activities of ALT and AST, and the liver was excised for assessing Cu/Zn superoxide dismutase (SOD) activity, GSH and protein concentrations and also for immunoblotting. Portions of the livers were used for histology and immunohistochemistry.


RESULTS
Pretreatment with rutin and, to a lesser extent, with quercetin significantly reduced the activity of plasma transaminases and improved the histological signs of acute liver damage in CCl(4)-intoxicated mice. Quercetin prevented the decrease in Cu/Zn SOD activity in CCl(4)-intoxicated mice more potently than rutin. However, it was less effective in the suppression of nitrotyrosine formation. Quercetin and, to a lesser extent, rutin attenuated the inflammation in the liver by down-regulating the CCl(4)-induced activation of nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α) and cyclooxygenase (COX-2). The expression of inducible nitric oxide synthase (iNOS) was more potently suppressed by rutin than by 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 an equivalent dose. Quercetin more potently suppressed the expression of transforming growth factor-β1 (TGF-β1) than rutin.


CONCLUSIONS
Rutin exerts stronger protection against nitrosative stress and hepatocellular damage but has weaker antioxidant and anti-inflammatory activities and antifibrotic potential than quercetin, which may be attributed to the presence of a rutinoside moiety in position 3 of the C ring.
Department of Chemistry and Biochemistry, University of Rijeka, Rijeka, Croatia. robertd@medri.hr
Robert
R
Domitrović
Hrvoje
H
Jakovac
Vanja
V
Vasiljev Marchesi
Sanda
S
Vladimir-Knežević
Olga
O
Cvijanović
Zarko
Z
Tadić
Zeljko
Z
Romić
Dario
D
Rahelić
D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry; D002252:Carbon Tetrachloride Poisoning / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009569:Nitric Oxide / Q000737:chemistry; D018384:Oxidative Stress / Q000187:drug effects; D010851:Picrates / Q000737:chemistry; D011794:Quercetin / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D012431:Rutin / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*
D001713:Biphenyl Compounds; D016166:Free Radical Scavengers; D010851:Picrates; D009569:Nitric Oxide; D012431:Rutin; D011794:Quercetin; C004931:1,1-diphenyl-2-picrylhydrazyl