The flavonoid quercetin ameliorates liver damage in rats with biliary obstruction


      Background/Aims: Our aim was to investigate whether the antioxidant quercetin might protect against liver injury in chronically biliary obstructed rats.
      Methods: Secondary biliary cirrhosis was induced by 28 days of bile duct obstruction. Animals received quercetin at 75, 150 and 300 μmol · kg body wt−1 · day−1 i.p. through the experimental period or at 150 μmol · kg body wt−1 · day−1 i.p. for the last 2 weeks.
      Results: Bile duct obstruction resulted in a decrease in the activities of antioxidant enzymes. Liver oxidised/reduced (GSSG/GSH) glutathione ratio, hepatic and mitochondrial thiobarbituric acid reactive substances (TBARS) and collagen content were significantly increased and a marked fibrosis and bile ductular proliferation was observed. Quercetin corrected the reduction in glutathione concentration and partially prevented the increase in collagen concentration, TBARS and GSSG/GSH ratio. Treatment resulted in a significant preservation of the activities of antioxidant enzymes, a less pronounced fibrosis and a marked inhibition of bile ductular proliferation. Maximal effects were reached with the intermediate quercetin dose given for 2 or 4 weeks.
      Conclusions: Quercetin reduces liver oxidative damage, ductular proliferation and fibrosis in biliary-obstructed rats. These effects suggest that it might be a useful agent to preserve liver function in patients with biliary obstruction.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Hunt DR
        The identification of risk factors and their application to the management of obstructive jaundice.
        Aust N J Surg. 1980; 50: 476-480
        • Sokol RJ
        Lipid peroxidation in cholestasis.
        in: Paumgartner G Stiehl A Gerok W Pediatric Cholestasis Dordrecht Kluwer. 1992: 75-80
        • Tasi LY
        • Lee KT
        • Tsai SM
        • Lee SC
        • Yu SH
        Changes of lipid levels in blood and liver tissues of patients with obstructive jaundice.
        Clin Chim Acta. 1993; 215: 41-50
        • Singh S
        • Shackleton G
        • Ah Sing E
        • Chakraborty J
        • Bailey ME
        Antioxidant defenses in the bile duct-hgated rat.
        Gastroenterology. 1992; 103: 1625-1629
        • Krahenbuhl S
        • Talos C
        • Lauteburg BH
        • Reichen J
        Reduced antioxidative capacity in liver mitochondria from bile duct ligated rats.
        Hepatology. 1995; 22: 607-612
        • Forestier M
        • Solioz M
        • Isbeki F
        • Talos F
        • Reichen J
        • Krahenbuhl S
        Hepatic mitochondrial pioliferation in rats with secondary biliary cirrhosis time courses and mechanisms.
        Hepatology. 1997; 26: 386-391
        • Muriel P
        • Suarez OR
        • Gonzalez PM
        • Zuñiga L
        Protective effect of S-adenosylmethionine on liver damage induced by biliary obstruction in rats a histological, ultrastructural and biochemical study.
        J Hepatol. 1994; 21: 95-102
        • Gonzalez-Correa JA
        • De la Cruz JP
        • Martin-Aurioles E
        • Lopez-Egea M
        • Ortiz P
        • Sánchez de la Cuesta F
        Effects of S-adenosyl-L-methionine on hepatic and renal oxidative stress in an experimental model of acute biliary obstruction in rats.
        Hepatology. 1997; 26: 121-127
        • Pastor A
        • Collado PS
        • Almar M
        • Gonzalez-Gallego J
        Microsomal function in biliary obstructed rats effects of S-adenosylmethionine.
        J Hepatol. 1996; 24: 353-359
        • Pastor A
        • Collado PS
        • Almar M
        • Gonzalez-Gallego J
        Antioxidant enzyme status in biliary-obstructed rats effects of N-acetylcysteine.
        J Hepatol. 1997; 27: 363-367
        • Pace-Asciak CR
        • Hahn S
        • Diamandis EP
        • Soleas G
        • Goldberg DM
        The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation in eicosanoid synthesis implication for protection against coronary heart disease.
        Clin Chim Acta. 1995; 235: 207-219
        • Jang M
        • Cai L
        • Udeani GO
        • Slowing KV
        • Thomas CF
        • Beecher CWW
        • et al.
        Cancer chemopreventive activity of resveratrol, a natural product derived from grapes.
        Science. 1997; 275: 218-221
        • Jovanovic SV
        • Steenken S
        • Simic MG
        • Hara Y
        Antioxidant properties of flavonoids reduction potentials and electron transfer reactions of flavonoid radicals.
        in: Rice Evans C Packer L Flavonoids in Health and Disease. Marcel Dekker, New York1998: 137-161
        • Kawada N
        • Seki S
        • Inoue M
        • Kuroki T
        Effect of antioxidants, resveratrol, quercetin, and N-acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells.
        Hepatology. 1998; 27: 1265-1274
        • Huk I
        • Brovkovich V
        • Nanobash V
        • Weigel G
        • Neumayer C
        • Partyka L
        • et al.
        Bioflavonoid quercetin scavenges superoxide and increases nitric oxide concentration in ischaemia-reperfusion injury an experimental study.
        Br J Surg. 1998; 85: 1080-1085
      1. National Academy of Sciences The Guiding Principles for Research Involving Animals Bethesda, MD.
        National Institutes of Health. 1991;
        • Lowry OH
        • Rosebrough NJ
        • Farr AL
        • Randall AJ
        Protein measurement with the Pholin phenol reagent.
        J Biol Chem. 1951; 193: 265-275
        • Hissin PJ
        • Hill R
        A fluorimetric method for determination of oxidised and reduced glutathione in tissues.
        Anal Biochem. 1976; 74: 214-226
        • Misra HP
        • Fridovich I
        The role of superoxide anion in the autooxidation of epinephrine and a simple assay for superoxide dismutase.
        J Biol Chem. 1972; 247: 3170-3175
        • Aebi HE
        in: Bergmeyer HU Methods of Enzymatic Analysis, Vol 3. Verlag Chemie, Weimheim1983: 273-286
        • Flohe L
        • Gunsler WA
        Glutathione peroxidase.
        Methods Enzymol. 1984; 105: 115-121
        • Ohkawa H
        • Ohnishi N
        • Yagi K
        Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction.
        Anal Biochem. 1979; 95: 351-358
        • Aguilar-Delfin I
        • López-Barrera F
        • Hernandez-Muñoz R
        Selective enhancement of lipid peroxidation in plasma membrane in two experimental models of liver regeneration partial hepatectomy and acute CCl4 administration.
        Hepatology. 1996; 24: 657-662
        • Cattell V
        • Cook T
        • Moncada S
        Glomeruli synthetise nitrite in experimental nephrotoxic nephritis.
        Kidney Int. 1990; 38: 1056-1060
        • Rojkind M
        • Gonzalez E
        An improved method for determining specific radioactivities of proline 14C and hydroxyproline 14C in collagen and non-collagenous proteins.
        Anal Biochem. 1974; 57: 1-7
        • Aleynik SI
        • Leo MA
        • Ma X
        • Aleynik MK
        • Lieber CS
        Polyenyl-phosphatidylcholine prevents carbon tetrachloride-induced lipid peroxidation while it attenuates liver fibrosis.
        J Hepatol. 1997; 27: 554-561
        • Snedecor GW
        • Cochran WG
        Statistical Methods.
        Ames Iowa State University. 1980; : 185-191
        • Parola M
        • Leonarduzzi G
        • Robino G
        • Albano E
        • Poli G
        • Dianzani MU
        On the role of lipid peroxidation in the pathogenesis of liver damage induced by long-standing cholestasis.
        Free Radical Biol Med. 1996; 20: 351-359
        • Gasso M
        • Rubio M
        • Varela G
        • Cabre M
        • Caballeria J
        • Alonso E
        • et al.
        Effects of S-adenosylmethionine on lipid peroxidation and liver fibrogenesis in carbon tetrachloride-induced cirrhosis.
        J Hepatol. 1996; 25: 200-205
        • Saperstein LA
        • Jirtle RL
        • Farouk M
        • Thompson HT
        • Chung KS
        • Meyers WC
        Transforming growth factor-β1 and mannose 6-phosphate/insulin like growth factor-II receptor expression during intrahepatic bile duct hyperplasia and biliary fibrosis in the rat.
        Hepatology. 1994; 19: 412-417
        • Lee KS
        • Buch M
        • Houglum K
        • Chojkier M
        Activation of hepatic stellate cells by TGFα and collagen type I is mediated by oxidative stress trough c-myb expression.
        J Clin Invest. 1995; 96: 2461-2468
        • Poli G
        • Parola M
        Oxidative damage and fibrogenesis.
        Free Radical Biol Med. 1997; 22: 287-305
        • Nagi P
        • Kiss A
        • Schnur J
        • Thorgeirsson SS
        Dexamethasone inhibits the proliferation of hepatocytes and oval cells but not bile duct cells in rat liver.
        Hepatology. 1998; 28: 423-429
        • Leonarduzzi G
        • Scavazza A
        • Biasi F
        • Chiarpotto E
        • Carmandola S
        • Vogel S
        • et al.
        The lipid peroxidation end-product 4-hydroxy-2,3-nonenal up-regulates transforming growth factor betal expression in the macrophage lineage a link between oxidative injury and fibrosclerosis.
        FASEB J. 1997; 11: 851-857
        • Camps J
        • Bargallo T
        • Gimenez A
        • Alie S
        • Caballeria J
        • Pares A
        • et al.
        Relationship between hepatic lipid peroxidation and fibrogenesis in carbon tetrachloride-treated rats effect of zinc administration.
        Clin Sci. 1992; 83: 695-700
        • Bedossa P
        • Houglum K
        • Trautwein C
        • Holstege A
        • Chjokier M
        Stimulation of collagen α(I) gene expression is associated with lipid peroxidation in hepatocellular injury a link to tissue fibrosis?.
        Hepatology. 1994; 19: 1262-1271
        • Corrales F
        • Gimenez A
        • Alvarez L
        • Caballeria J
        • Pajares MA
        • Andreu H
        • et al.
        S-adenosylmethionine treatment prevents carbon tetrachloride-induced S-adenosylmethionine synthetase inactivation and attenuates liver injury.
        Hepatology. 1992; 16: 1022-1027
        • Sanchez-Góngora E
        • Ruiz F
        • Mingorance J
        • An W
        • Corrales FJ
        • Mato JM
        Interaction of liver methionine adenosyltransferase with hydroxyl radical.
        FASEB J. 1997; 11: 1013-1019
        • Ruíz F
        • Corrales FJ
        • Miqueo C
        • Mato JM
        Nitric oxide inactivates rat hepatic methionine adenosyltransferase in vivo by Snitrosylation.
        Hepatology. 1998; 28: 1051-1057
        • Mayoral P
        • Criado M
        • Hidalgo F
        • Flores O
        • Arevalo MA
        • Eleno N
        • et al.
        Effects of chronic nitric oxide activation or inhibition on early hepatic fibrosis in rats with bile duct ligation.
        Clin Sci. 1999; 96: 297-305
        • Cheis M
        • Schwaller R
        Inhibition of constitutive endothelial NO-synthase activity by tannin and quercetin.
        Biochem Pharmacol. 1995; 49: 495-501
        • Castilla-Cortazar I
        • Garcia M
        • Muguerza B
        • Quiroga J
        • Perez R
        • Santidrian S
        • et al.
        Hepatoprotective effect of insulin-like growth factor I in rats with carbon tetrachloride-induced cirrhosis.
        Gastroenterology. 1997; 113: 1682-1691
        • Hodgson EK
        • Fridovich I
        The interaction of bovine erythrocyte superoxide dismutase with hydrogen peroxide inactivation of the enzyme.
        Biochemistry. 1975; 14: 5294-5299
        • Blum J
        • Fridovich I
        Inactivation of glutathione peroxidase by superoxide radical.
        Arch Biochem Biophys. 1985; 240: 500-508
        • Kinter MT
        • Roberts RJ
        Glutathione consumption and glutathione peroxidase inactivation in fibroblast cell lines by 4-hydroxy-2-nonenal.
        Free Radical Med Biol. 1996; 21: 457-462
        • Ji LL
        • Stratman W
        • Lardy HA
        Antioxidant enzyme systems in rat liver and skeletal muscle Influences of selenium deficiency, chronic training and acute exercise.
        Arch Biochem Biophys. 1988; 263: 150-160
        • Polavarapu R
        • Spitz DR
        • Sim JE
        • Follansbee MH
        • Oberley LW
        • Rahemtulla A
        • et al.
        Increased lipid peroxidation and impaired antioxidant enzyme function is associated with pathological liver injury in experimental alcoholic liver disease in rats fed diets high in corn oil and fish oil.
        Hepatology. 1998; 27: 1317-1323
        • Swart PJ
        • Hirano T
        • Kuipers ME
        • Ito Y
        • Smit C
        • Hashida M
        • et al.
        Targeting of superoxide dismutase to the liver results in antrinflammatory effects in rats with fibrotic livers.
        J Hepatol. 1999; 31: 1034-1043
        • Cao G
        • Sofic E
        • Prior RL
        Antioxidant and prooxidant behavior of flavonoids structure-activity relationships.
        Free Radical Biol Med. 1997; 22: 749-760
        • Formica JV
        • Regelson W
        Review of the biology of quercetin and related bioflavonoids.
        Food Chem Toxic. 1995; 33: 1061-1080
        • Ahmad MS
        • Fazal F
        • Rahman A
        • Hadi SM
        • Parish JA
        Activities of flavonoids for the cleavage of DNA in the presence of Cu(II) correlation with geneiation of active oxygen species.
        Carcinogenesis. 1992; 13: 605-608
        • Hodnick WF
        • Duval DL
        • Pardinr RS
        Inhibition of mitochondrial iespiration and cyanide-stimulated generation of reactive oxygen species by selected flavonoids.
        Biochem Pharmacol. 1994; 47: 573-580