|
Protective effects of quercetin on liver injury induced by ethanol
Xi Chen
Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, 151 Malianwa North Road, Haidian District, Beijing 100193, China
| Date of Submission | 13-Dec-2009 |
| Date of Decision | 08-Jan-2010 |
| Date of Web Publication | 30-Apr-2010 |
Correspondence Address:
Xi Chen
Institute of Medicinal Plant Development, Beijing
China
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0973-1296.62900
 Abstract | | |
Quercetin, a natural compound of multiple origins, has broad biopharmacological effects, such as antioxidant, directly scavenging free radical, and hepatoprotectivity effects. This study is designed to investigate the interveneous effect of quercetin on liver injury induced by ethanol in rats. The rats that were orally treated with 50% ethanol for continuous ten days, which resulted in cell necrosis, fibrosis and inflammatory infiltration, were included in this study. Higher contents of AST, ALT ADH, γ-GT, TG in plasma and MDA in liver tissue, and lower content of GSH in liver tissue were highlighted in ethanol-treated rats when compared with healthy ones. The levels of cytokines such as IL-1β, IL-1, IL-6, IL-8, and TNF-α in rats plasma were also significantly enhanced, and level of IL-10 was obviously lowered through ethanol treatment. By preventive and synchronism treatment with quercetin for fourteen days, the contents of AST, ALT ADH, γ-GT, TG and MDA, and levels of IL-1β, IL-1, IL-6, IL-8, and TNF-α were significantly reduced, whereas GSH and level of IL-10 were obviously increased. It may be deduced that quercetin, by multiple mechanisms interplay, demonstrated somewhat protective effect on liver injury induced by ethanol in rats. Keywords: Quercetin, ethanol, liver injury, protective effect, rat
How to cite this article:
Chen X. Protective effects of quercetin on liver injury induced by ethanol. Phcog Mag 2010;6:135-41 |
| Introduction | |  |
Alcoholic liver disease (ALD) remains one of the most common causes of chronic liver disease, [1] while ASD and chronic viral hepatitis are the leading causes of cirrhosis and hepatocellular carcinoma worldwide. [2],[3] However, the mechanism of ethanol-induced liver injury associated with fatty liver, hepatitis, cirrhosis etc were not fully understood. Metallothionein is an intracellular protein, which is capable of binding metals and scavenging reactive oxygen species. [4],[5] The main synthesis place of metallothionein is liver tissue, [6] and the studies revealed that ethanol is a potent inducer of liver metallothionein. [7],[8] It is reported that several mediator systems are correlated with the development of ALD from fatty liver to advanced liver injury, such as inflammation [9] and necrosis. Alcoholic fatty liver is more susceptible to many inflammatory stimuli, [10] the bacterial endotoxins that are mainly involved in the inflammatory process. Therefore, in the experimental models of ethanol-induced liver injury, it has been demonstrated that endotoxin levels are correlated with liver pathology. [11],[12] Moreover, oxidative stress or ischemic damage also seem to aggravate ethanol-induced hepatic inflammation. [13] Experimental evidences demonstrate that inflammatory reactions and oxidative stress play a major role in ethanol-induced liver injury. [14],[15]
Although some important progresses have been made in investigating the pathogenesis of ALD, current treatments for this disease are not satisfactory. In recent years, it has been reported that the herbal drugs play a significant role in the therapy of hepatic disorders. [16],[17],[18] Quercetin, a flavonoid constituent [19] [Figure 1], is found in many herbal drugs and foods, [20] demonstrating broad biopharmacological properties. [21] Quercetin demonstrates antioxidant defense by scavenging free radicals and inhibiting various molecules oxidation, [22],[23] being an useful agent for protecting various neuronal cells against oxidative stress. [24],[25] Quercetin has preliminarily showed protective effect on liver injury in rats with carbon tetrachloride-induced cirrhosis, [26] but the study to investigate its antioxidant and hepatoprotective effects on ethanol-induced liver injury in animal model has been not carried out. The antioxidant defense of quercetin against oxidative stress action [24],[25] is the main mechanism of its protective effect on ethanol-induced liver injury. [14],[15] The purpose of this study is to assess the protective effect of quercetin on ethanol-induced acute liver injury in rats. Hepatoprotectivity can be achieved by eating foods which are rich in quercetin for reducing liver degeneration due to ethanol consumption
| Materials and Methods | | |
Chemicals and reagents
Dehydrated ethanol was purchased from Beijing Chemical factory (Beijing, China). Quercetin (Purity>99%) was purchased from National Institute for the Control of Pharmaceutical and Biological Products (Beijing, PR China); the Assay Kits of glutamate-pyruvate transaminase (ALT), glutamic-oxal(o)acetic transaminase (AST) and triglyceride (TG) were purchased from Zhongsheng BeiKong Biological Technology Limited Corporation (Beijing, China); the Assay Kits of ethanol dehydrogenase (ADH) was purchased from Huili Biological Technology Limited Corporation (Changchun, China); the Assay Kits of nitric oxide(NO) γ-L- glutamyltranspeptidase (γ-GT, glutathion (GSH) and malondialdehyde (MDA) were purchased from Jiancheng Biological Engineering Institute (Nanjing, China); the Assay Kits of interleukin-1β (IL-1β), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10) were from Schering-Plough Research Institute (Kenilworth, NJ). The Assay Kit of tumor necrosis factor α (TNF-α) was from BD Pharmingen (Los Angeles, CA). All other chemicals were of analytical grade.
Animals and treatments
With the objective of finding out the protective effect of quercetin on acute liver injury in experimental animals induced by ethanol, [27],[28] fifty male Wistar rats, weighing 240 ± 20 g, were purchased from the Animal Center of Shanhai SLAC Experimental and Animal Company (Shanghai, China). Animals were kept in an environmentally controlled breeding room (temperature: 24 ± 2°C, humidity: 60 ± 5%, 12 h dark-light cycles) for one week before the experiment. The rats were fed standard laboratory chow with water ad. Libitum. All animals were randomly divided into five groups including control group (CG), ethanol-treated group (EG), low dose group of quercetin (LG), middle dose group of quercetin(MG) and high dose group of quercetin (HG). The LG, MG and HG were treated with quercetin at a dose of 5 mg/kg, 10 mg/kg and 20 mg/kg by body weight, respectively, for continuous fourteen days. Fifty percent of ethanol (v/v) was administrated at a dose of 5g/kg after 2.5 h of quercetin administration from the fifth day for continuous ten days. An equal amount of distilled water was orally administrated for EG group for continuous four days, and 50% ethanol (v/v) at a dose of 5 g/kg from the fifth day for continuous ten days. The CG received an equal amount of distilled water for continuous fourteen days. On the fifteenth day, blood samples and liver tissues were collected from the rats under anesthesia for experimental analysis after 12 h of final treatment.
Assay of cytokines and liver enzyme levels in rat serum
Blood samples were obtained from inferior caval vein, and serum IL-1β, IL-1, IL-6, IL-8, IL-10 and TNF-α amounts were measured by ELISA (R and D System, Abingdon, UK). Hepatocyte damage was evaluated by measuring serum enzyme activities of AST and ALT using an automated Synchron LX20 Beckman-Coulter according to the IFCC procedure [29],[30] with the addition of pyridoxal phosphate.
Assay of ADH, g-GT and TG levels in rat plasma
All blood samples were collected from inferior caval vein of rats and centrifuged at 3000 rpm for 15 min, the supernatants were taken for ADH, γ-GT and TG assay. The activities of ADH, γ-GT and TG were measured by an automated Synchron LX20 Beckman-Coulter using diagnostic EIA kits according to the manufacturer's instructions. [31]
Assay of MDA and GSH levels in rat liver
All liver tissues were perfused with 0.9% NaCl before cutting from rats for subtracting blood stain, and were homogenized on ice in 0.9% NaCl. The homogenates were centrifuged at 4500 rpm for 15 min at 4°C and the supernatants were taken for GSH and MDA assay. [32] The activities of GSH and MDA were measured by an Automated Synchron LX20 Beckman-Coulter using diagnostic EIA kits according to the manufacturer's instructions. [33],[34]
Statistical analysis
All data were expressed as means ±S.D. Significant differences among the groups were determined by one-way ANOVA analysis of variance using the SPSS 11.0 statistical analysis program (SPSS Institute, Cary, NC, USA). The P values<0.05 were considered as statistically significant.
| Results | | |
Effects of quercetin on cytokines in rats with ethanol-induced liver injury
In comparison with control group rats, the levels of IL-1β, IL-6, IL-8, and TNF-α were significantly elevated in rat serum administrated with ethanol, except IL-10 that showed an obvious decrease in serum level(P < 0.01). The quercetin-treated rats demonstrated the serum levels of IL-1β, IL-1, IL-6, IL-8, and TNF-α were obviously lowered, except IL-10 that showed an obvious increase compared with the ethanol administrated rats, and the effects of HG and MG were more remarkable [Figure 2]
Effect of quercetin on levels of ALT, AST, ADH, -GT and TG in rats with ethanol-induced liver injury
It is demonstrated that ethanol-treated rats produced severe liver injury by significantly increasing the serum levels of AST and ALT compared with that of the CG. All the rats treated with different doses of quercetin showed significantly decreased levels of ALT and AST compared with that of EG [Figure 3] a & b. The serum levels of ADH, γ-GT and TG were also significantly elevated by ethanol administration. However, the rats treated with quercetin showed an obvious decrease in ADH, γ-GT and TG levels compared with that of EG [Figure 3] c, d & e.
Effects of quercetin on levels of GSH and MDA in rats with ethanol-induced liver injury
The hepatic GSH level of rats administered with ethanol alone was found to be significantly lowered compared with that of CG, while rats treated with quercetin at a dose of 12 g/kg exhibited significantly increased hepatic GSH levels. The treatment groups of quercetin at a dose of 2g/kg or 6 g/kg almost did not prevent the decreases in hepatic GSH levels in comparison with that of EG [Figure 4]. A significant increase in hepatic MDA level was observed in ethanol-treated rats. However, ethanol-induced elevation in hepatic MDA level was lowered significantly when quercetin was administrated to the rats at a dose of 12g/kg, The MG and LG did not exhibit this effect [Figure 4] compared with EG.
Effects of quercetin on levels of NO in rats with ethanol-induced liver injury
It is reported that an acute high dose of ethanol induced an increase in NO levels. [35] It is found that ethanol treatment can significantly enhance the NO levels in rats plasma compared with that of CG. When different doses of quercetin were administrated, the levels of NO gradually decreased in CG rats. rats [Figure 5].
| Discussion | | |
Alcoholic liver disease (ALD) is associated with the overproduction of proinflammatory cytokines such as interleukin-1β(IL-1β), IL-1, IL-8 and IL-6.[36],[37],[38],[39],[40],[41] These cytokines play a vital pathological role in the development of ALD, as demonstrated commonly in animal models, and mediates monocyte/Kupffer cell activation, elevated vascular permeability, necrosis and/or apoptosis of hepatocytes, over expression of adhesion molecules on endothelial cells, and the activation and chemoattraction of neutrophils and mononuclear cells. [42],[43] From these studies, it can be found that ethanol treatment remarkably enhanced the levels of IL-1β, IL-1, IL-6 and IL-8 in rat serum; however, quercetin administration inhibited this elevations which is attributed to the significant reduction in the serum levels of IL-1β, IL-1, IL-6 and IL-8.
IL-10 is a potent anti-inflammatory cytokine that endogenously controls the synthesis of several proinflammatory mediators. [44] The levels of IL-10 in serum are obviously lowered with ethanol treatment, whereas quercetin administration has inhibited the reduction in the levels of IL-10, which is responsible for anti-inflammatory action and relieving liver injury in rats.
Ii is demonstrated that an acute high dose of ethanol consumption results in an elevation in NO levels, [35] the same increase in NO occurs in man who follow binge drinking. [45] The overproduction of NO is an important cause of inflammation reaction. [46],[47] Moreover, the pathological role of TNF-α in ethanol- and endotoxin-caused liver injury, derived from experimental models, has also been demonstrated. On the one hand, chronic ethanol treatment in mice is correlated with elevatedexpression of TNF-α mRNA in the liver,[48] and mice with a targeted disruption of TNF receptor 1 are kept from ALD. [49] On the other hand, it is reported that, liver injury is essentially mediated by TNF-α in the GAL plus LPS model.[50] In this study, it is observed that levels of NO and TNF-α in rats serum were significantly enhanced by ethanol, whereas the increases were obviously inhibited by quercetin treatment, supporting the hepatoprotective effect of quercetin on ethanol-treated rats, which is partly attributed to its anti-inflammation action.
As we all know, liver Injury after ethanol treatment is a common phenomenon, and the obvious indicator of liver injury is the leakage of cellular enzymes into plasma. [51] The increase in serum enzymes levels associated with ALT and AST has been observed in ethanol-treated rats, which shows the enhanced permeability, injury and necrosis of hepatocytes. [52] The hepatoprotective effect of quercetin on liver injury is well evident, which significantly inhibits the increases in these enzymes levels caused by ethanol for keeping the liver structural integrity from ethanol injury.
Many researchers have demonstrated that ethanol-induced liver injuries are related to free radicals and oxidative stress. [53],[54],[55] Lipid peroxidation plays an important role in oxidative stress injury for liver, [56] which was determined indirectly by evaluating the enhances in MDA levels [57] and the decreases in GSH levels. [58] In this study, we observed a higher level of MDA and a lower level of GSH in the liver of ethanol-treated rats, which has been recognized as a proof to support the hypothesis that reactive oxygen intermediates, generated from the metabolism of ethanol, are attributed to lipid peroxidation and glutathione oxidation induced the ethanol hepatotoxicity. Quercetin-administrated rats showed significantly increased GSH level and decreased MDA level when compared with ethanol-treated rats,demonstrating the antioxidant effects of quercetin. We conclude that the hepatoprotective effect of quercetin may be partly due to its antioxidant activity.
Simultaneously, some studies demonstrated that the physiological factors that change liver ADH activity cause alteration in the rate of ethanol metabolism. [59],[60],[61] These evidences support the opinion that the level of ADH is a key factor controlling the metabolic rate of ethanol in vivo. The activity of γ-GT is an indicator of hepatic damage, which is usually used as sensitive marker in the diagnosis of hepatic diseases. [62] In this study, the serum levels of ADH and γ-GT were significantly enhanced by ethanol treatment, showing higher concentrations of ethanol in blood and certain injury in rat liver. In quercetin-treated rats, the serum levels of ADH and γ-GT were decreased significantly when compared with ethanol-treated rats. These results may support the fact that hepatoprotective effect of quercetin is partially attributed to its effect of accelerating ethanol metabolism and excretion.
In conclusion, the above analysis well supports the protective effect of quercetin on ethanol-induced acute liver injury in rats. We conclude that quercetin, by multiple mechanisms interplay, demonstrates hepatoprotective effect on liver-injury induced by alcohol, by increasing ethanol metabolizing enzyme activities, increasing antioxidant system activities against oxidative stress, lowering the expressions of proinflammation cytokines. This study also suggests the necessity of selecting some natural compounds for ALD therapy.
| References | | |
| 1. | Diehl AM. Liver disease in alcohol abusers: clinical perspective. Alcohol 2002;27:7-11.  |
| 2. | Esteban R. Management of chronic hepatitis B: An overview. Semin Liver Dis 2002;22:1-6. |
| 3. | Walker MP, Appleby TC, Zhong W, Lau JY, Hong Z. Hepatitis C virus therapies: Current treatments, targets and future perspectives. Antivir Chem Chemother 2003;14:1-21. |
| 4. | Sato M, Bremner I. Oxygen free radicals and metallothionein. Free Radic Biol Med 1993;14:325-37. |
| 5. | Floriaρczyk B. Function of metallothionein in the body. Postepy Hig Med Dosw 1996;50:375-82 . |
| 6. | Floriaρczyk B, Stryjecka-Zimmer M. Induction of metallothioneins by ethanol and morphine. Ann Univ Mariae Curie Sklodowska Med 2001;56:183-7. |
| 7. | Carey LC, Berbιe PL, Coyle P, Philcox JC, Rofe AM. Zinc treatment prevents lipopolysaccharide-induced teratogenicity in mice. Birth Defects Res A Clin Mol Teratol 2003;67:240-5. |
| 8. | Carey LC, Coyle P, Philcox JC, Rofe AM. Zinc supplementation at the time of ethanol exposure ameliorates teratogenicity in mice. Alcohol Clin Exp Res 2003;27:107-10. |
| 9. | Jδrvelδinen HA, Fang C, Ingelman-Sundberg M, Lukkari TA, Sippel H, Lindros KO. Kupffer cell inactivation alleviates ethanol-induced steatosis and CYP2E1 induction but not inflammatory responses in rat liver. J Hepatol 2000;32:900-10. |
| 10. | Stewart S, Jones D, Day CP. Alcoholic liver disease: New insights into mechanisms and preventative strategies. Trends Mol Med 2001;7:408-13. |
| 11. | Schenker S, Bay MK. Alcohol and endotoxin: Another path to alcoholic liver injury? Alcohol Clin Exp Res1995;19:1364-6. |
| 12. | Jδrvelδinen HA, Fang C, Ingelman-Sundberg M, Lindros KO. Effect of chronic coadministration of endotoxin and ethanol on rat liver pathology and proinflammatory and anti-inflammatory cytokines. Hepatology 1999;29:1503-10. |
| 13. | Tsukamoto H, Lin M, Ohata M, Giulivi C, French SW, Brittenham G. Iron primes hepatic macrophages for NF-kappaB activation in alcoholic liver injury. Am J Physiol 1999;277:1240-50. |
| 14. | Achliya GS, Wadodkar SG, Dorle AK. Evaluation of hepatoprotective effect of Amalkadi Ghrita against carbon tetrachloride-induced hepatic damage in rats. J Ethnopharmacol 2004;90:229-32. |
| 15. | Rao GM, Rao CV, Pushpangadan P, Shirwaikar A. Hepatoprotective effects of rubiadin; A major constituent of Rubia cordifolia Linn. J Ethnopharmacol 2006;103:484-90. |
| 16. | Tilg H, Diehl AM. Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med 2000;3439:1467-76. |
| 17. | Albano E. Free radicals and alcohol-induced liver injury. In: Sherman CD, Preedy VR, Watson RR, editors. Ethanol and the Liver. London: Taylor and Francis; 2002. P. 153-90. |
| 18. | Arteel GE. Oxidants and antioxidants in alcohol-induced liver disease. Gastroenterology 2003;124:778-90. |
| 19. | Deng YR, Ding L, Wu SX, Wang HQ. Studies on chemical constituents in herb of Lamium maculatum var. kansuense (II). Zhongguo Zhong Yao Za Zhi 2005;30:272-4. |
| 20. | Duthie SJ, Dobson VL. In vitro Dietary flavonoids protect human colonocyte DNA from oxidative attack. Eur J Nutr 1999;38:28-34. |
| 21. | Sasaki M, Nakamura H, Tsuchiya S, Horie S, Kashiwayanagi M, Saito T, et al. Quercetin-induced PC12 cell death accompanied by caspase-mediated DNA fragmentation. Biol Pharm Bull 2007;30:682-6. |
| 22. | Williams RJ, Spencer JP, Rice-Evans C. Flavonoids: Antioxidants or signalling molecules? Radic Biol Med 2004;36:838-49. |
| 23. | Aviram M, Fuhrman B. Wine flavonoids protect against LDL oxidation and atherosclerosis. Ann N Y Acad Sci 2002;957:146-61. |
| 24. | Middleton E Jr, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer. Pharmacol Rev 2000;52:673-751. |
| 25. | Bastianetto S, Quirion R. Natural extracts as possible protective agents of brain aging. Neurobiol Aging 2002;23:891-7. |
| 26. | Pavanato A, Tuρσn MJ, Sαnchez-Campos S, Marroni CA, Llesuy S, Gonzαlez-Gallego J, et al. Effects of quercetin on liver damage in rats with carbon tetrachloride-induced cirrhosis. Dig Dis Sci 2003;48:824-9. |
| 27. | Lambert JC, Zhou Z, Wang L, Song Z, McClain CJ, Kang YJ. Prevention of alterations in intestinal permeability is involved in zinc inhibition of acute ethanol-induced liver damage in mice. J Pharmacol Exp Ther 2003;305:880-6. |
| 28. | Zhou Z, Sun X, Lambert JC, Saari JT, Kang YJ. Metallothionein-independent zinc protection from alcoholic liver injury. Am J Pathol 2002;160:2267-74. |
| 29. | ergmeyer HU, Hψrder M, Rej R. IFCC methods for aspartate aminotransferase. J Clin Chem Clin Biochem 1986;24:497-510. |
| 30. | Bergmeyer HU International federation of clinical chemistry. Scientific committee. Expert panel on enzymes. IFCC document stage 2, draft 1; 1979-11-19 with a view to an IFCC recommendation. IFCC methods for the measurement of catalytic concentration of enzymes. Part 3. IFCC method for alanine aminotransferase. J Clin Chem Clin Biochem 1986;7:481-95. |
| 31. | Clemens DL, Halgard CM, Miles RR, Sorrell MF, Tuma DJ. Establishment of a recombinant hepatic cell line stably expressing alcohol dehydrogenase. Arch Biochem Biophys 1995;321:311-8. |
| 32. | Moldιus P, Hφgberg J, Orrenius S. Isolation and use of liver cells. Met Enzymol 1978;52:60-71. |
| 33. | Hochstein P, Utley H. Hydrogen peroxide detoxication by glutathione peroxidase and catalase in rat liver homogenates. Mol Pharmacol 1968;4:574-9. |
| 34. | Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979;95:351-8. |
| 35. | Baraona E, Shoichet L, Navder K, Lieber CS. Mediation by nitric oxide of the stimulatory effects of ethanol on blood flow. Life Sci 2002;70:2987-95. |
| 36. | McClain CJ, Cohen DA. Increased tumor necrosis factor production by monocytes in alcoholic hepatitis. Hepatology 1989;9:349-51. |
| 37. | Deviθre J, Content J, Denys C, Vandenbussche P, Schandene L, Wybran J, et al. Excessive in vitro bacterial lipopolysaccharide-induced production of monokines in cirrhosis. Hepatology 1990;11:628-34. |
| 38. | Deviere J, Content J, Denys C, Vandenbussche P, Schandene L, Wybran J, et al. High interleukin-6 serum levels and increased production by leucocytes in alcoholic liver cirrhosis. Correlation with IgA serum levels and lymphokines production. Clin Exp Immunol 1989;77:221-5. |
| 39. | Bird GL, Sheron N, Goka AK, Alexander GJ, Williams RS. Increased plasma tumor necrosis factor in severe alcoholic hepatitis. Ann Intern Med 1990;112:917-20. |
| 40. | Sheron N, Bird G, Koskinas J, Portmann B, Ceska M, Lindley I. Circulating and tissue levels of the neutrophil chemotaxin interleukin-8 are elevated in severe acute alcoholic hepatitis, and tissue levels correlate with neutrophil infiltration. Hepatology 1993;18:41-6. |
| 41. | Hill DB, Marsano LS, McClain CJ. Increased plasma interleukin-8 concentrations in alcoholic hepatitis. Hepatology 1993;18:576-80. |
| 42. | Mathurin P, Ganne-Carriι N, Poynard T, Trinchet JC. Pro-inflammatory cytokines in the pathogenesis of alcoholic hepatitis. Gastroenterol Clin Biol 1998;22:311-9. |
| 43. | Thurman RG. Alcoholic liver injury involves activation of Kupffer cells by endotoxin Am J Physiol 1998;275:605-11. |
| 44. | Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001;19:683-765. |
| 45. | Oekonomaki E, Notas G, Mouzas IA, Valatas V, Skordilis P, Xidakis C, et al. Binge drinking and nitric oxide metabolites in chronic liver disease. Alcohol Alcohol 2004;39:106-9. |
| 46. | Kilbourn RG, Griffith OW. Overproduction of nitric oxide in cytokine-mediated and septic shock. J Natl Cancer Inst 1992;84:827-31. |
| 47. | Russo C, Polosa R. TNF-alpha as a promising therapeutic target in chronic asthma: A lesson from rheumatoid arthritis. Clin Sci 2005;109:135-42. |
| 48. | Nanji AA, Zhao S, Sadrzadeh SM, Waxman DJ. Use of reverse transcription-polymerase chain reaction to evaluate in vivo cytokine gene expression in rats fed ethanol for long periods. Hepatology 1994;19:1483-7. |
| 49. | Yin M, Wheeler MD, Kono H, Bradford BU, Gallucci RM, Luster MI, et al. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology 1999;117:942-52. |
| 50. | Hishinuma I, Nagakawa J, Hirota K, Miyamoto K, Tsukidate K, Yamanaka T, et al. Involvement of tumor necrosis factor-alpha in development of hepatic injury in galactosamine-sensitized mice. Hepatology 1990;12:1187-91. |
| 51. | Baldi E, Burra P, Plebani M, Salvagnini M. Serum malondialdehyde and mitochondrial aspartate aminotransferase activity as markers of chronic alcohol intake and alcoholic liver disease. Ital J Gastroenterol 1993;25:429-32. |
| 52. | Goldberg DM, Watts C. Serum enzyme changes as evidence of liver reaction to oral alcohol. Gastroenterology 1965;49:256-61. |
| 53. | Morel Y, Barouki R. Repression of gene expression by oxidative stress. Biochem J 1999;342:481-96. |
| 54. | Jordγo AA Jr, Chiarello PG, Arantes MR, Meirelles MS, Vannucchi H. Effect of an acute dose of ethanol on lipid peroxidation in rats: Action of vitamin E. Food Chem Toxicol 2004;42:459-64. |
| 55. | Koch O, Farrι S, De Leo ME, Palozza P, Palazzotti B, Borrelo S, et al. Regulation of manganese superoxide dismutase (MnSOD) in chronic experimental alcoholism: Effects of vitamin E-supplemented and -deficient diets. Alcohol Alcohol 2000;35:159-63. |
| 56. | Slater TF. Free-radical mechanisms in tissue injury. Biochem J 1984;222:1. |
| 57. | Draper HH, Hadley M. Malondialdehyde determination as index of lipid peroxidation. Met Enzymol 1990;186:421-31. |
| 58. | Guerri C, Grisolia S. Influence of prolonged ethanol intake on the levels and turnover of alcohol and aldehyde dehydrogenases and glutathione. Adv Exp Med Biol 1980;126:365-84. |
| 59. | Rachamin G, MacDonald JA, Wahid S, Clapp JJ, Khanna JM, Israel Y. Modulation of alcohol dehydrogenase and ethanol metabolism by sex hormones in the spontaneously hypertensive rat. Effect of chronic ethanol administration. Biochem J 1980;186:483-90. |
| 60. | Plapp BV, Leidal KG, Smith RK, Murch BP. Kinetics of inhibition of ethanol metabolism in rats and the rate-limiting role of alcohol dehydrogenase. Arch Biochem Biophys 1984;230:30-8. |
| 61. | Cheema-Dhadli S, Halperin FA, Sonnenberg K, MacMillan V, Halperin ML. Regulation of ethanol metabolism in the rat. Biochem Cell Biol 1987;65:458-66. |
| 62. | Choi JS, Yoon TJ, Kang KR, Lee KH, Kim WH, Suh YH, et al. Glycoprotein isolated from Acanthopanax senticosus protects against hepatotoxicity induced by acute and chronic alcohol treatment. Biol Pharm Bull 2006;29:306-14. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
| This article has been cited by | | 1 |
Micro RNAs 26b, 20a inversely correlate with GSK-3 ß/NF-?B/NLRP-3 pathway to highlight the additive promising effects of atorvastatin and quercetin in experimental induced arthritis |
|
| Sherihan Salaheldin Abdelhamid Ibrahim, Lamia Said Kandil, Ghada M. Ragab, Shorouk M. El-Sayyad | | International Immunopharmacology. 2021; 99: 108042 | | [Pubmed] | [DOI] | | | 2 |
Phytochemical based sestrin2 pharmacological modulators in the treatment of adenocarcinomas |
|
| Abdullahi Alausa, Ugwu Chukwuebuka Victor, Ugwu Obiora Celestine, Ismail Abiodun Eweje, Toheeb Adewale Balogun, Rofiat Adeyemi, Mercy Olatinwo, Abdeen Tunde Ogunlana, Oladapo Oladipo, Barakat Olaleke | | Phytomedicine Plus. 2021; 1(4): 100133 | | [Pubmed] | [DOI] | | | 3 |
The effects of Papaver somniferum (Opium poppy) on health, its controversies and consensus evidence |
|
| Mahdiyeh Hedayati-Moghadam, Seyyed Ali Moezi, Toba Kazemi, Abdul Sami, Muhammad Akram, Rida Zainab, Mohammad Reza Khazdair | | Toxin Reviews. 2021; : 1 | | [Pubmed] | [DOI] | | | 4 |
Nonalcoholic fatty liver disease: The role of quercetin and its therapeutic implications |
|
| Maria Sotiropoulou, Ioannis Katsaros, Michail Vailas, Irene Lidoriki, GeorgeV Papatheodoridis, NikolaosG Kostomitsopoulos, Georgia Valsami, Alexandra Tsaroucha, Dimitrios Schizas | | Saudi Journal of Gastroenterology. 2021; 27(6): 319 | | [Pubmed] | [DOI] | | | 5 |
Nutraceutical Properties of Polyphenols against Liver Diseases |
|
| Jorge Simón, María Casado-Andrés, Naroa Goikoetxea-Usandizaga, Marina Serrano-Maciá, María Luz Martínez-Chantar | | Nutrients. 2020; 12(11): 3517 | | [Pubmed] | [DOI] | | | 6 |
Protective Effects of Quercetin on Livers from Mice Exposed to Long-Term Cigarette Smoke |
|
| Pedro A. Machado-Junior, Natália P. S. Araújo, Ana B. F. Souza, Thalles F. Castro, Michel Oliveira, Guilherme P. Costa, Natália A. Matos, Paula M. A. Vieira, André Talvani, Frank S. Bezerra, Sílvia D. Cangussú, Abdelwahab Omri | | BioMed Research International. 2020; 2020: 1 | | [Pubmed] | [DOI] | | | 7 |
Recent Advances in Liposomal Drug Delivery System of Quercetin for Cancer Targeting: A Mechanistic Approach |
|
| Sabya S. Das, Afzal Hussain, Priya R. Prasad Verma, Syed S. Imam, Mohammad A. Altamimi, Sultan Alshehri, Sandeep Kumar Singh | | Current Drug Delivery. 2020; 17(10): 845 | | [Pubmed] | [DOI] | | | 8 |
Extraction and Identification of Two Flavonoids in Phlomoides hyoscyamoides as an Endemic Plant of Iran: The Role of Quercetin in the Activation of the Glutathione Peroxidase, the Improvement of the Hydroxyproline and Protein Oxidation in Bile Duct-Ligate |
|
| Amir H. Doustimotlagh, Salman Taheri, Mahboubeh Mansourian, Mahdieh Eftekhari | | Current Computer-Aided Drug Design. 2020; 16(5): 629 | | [Pubmed] | [DOI] | | | 9 |
Hepatoprotective effect of Matricaria chamomilla aqueous extract against 1,2-Dimethylhydrazine-induced carcinogenic hepatic damage in mice |
|
| Salima Shebbo, Manal El Joumaa, Rawan Kawach, Jamilah Borjac | | Heliyon. 2020; 6(6): e04082 | | [Pubmed] | [DOI] | | | 10 |
Hepatoprotective effect of Moringa oleifera leaves aquatic extract against lead acetate–induced liver injury in male Wistar rats |
|
| Mohy E. Abdel Fattah, Hanan M. Sobhy, Areeg Reda, Heba M. A. Abdelrazek | | Environmental Science and Pollution Research. 2020; 27(34): 43028 | | [Pubmed] | [DOI] | | | 11 |
Crosstalk between obesity, diabetes, and alzheimer’s disease: Introducing quercetin as an effective triple herbal medicine |
|
| Shiva Ebrahimpour, Mansoureh Zakeri, Abolghasem Esmaeili | | Ageing Research Reviews. 2020; 62: 101095 | | [Pubmed] | [DOI] | | | 12 |
Hepatoprotective and antioxidant activity of quercetin loaded chitosan/alginate particles in vitro and in vivo in a model of paracetamol-induced toxicity |
|
| Virginia Tzankova,Denitsa Aluani,Magdalena Kondeva-Burdina,Yordan Yordanov,Feodor Odzhakov,Alexandar Apostolov,Krassimira Yoncheva | | Biomedicine & Pharmacotherapy. 2017; 92: 569 | | [Pubmed] | [DOI] | | | 13 |
Chitosan nanoparticles plus quercetin suppress the oxidative stress, modulate DNA fragmentation and gene expression in the kidney of rats fed ochratoxin A-contaminated diet |
|
| Mosaad A. Abdel-Wahhab,Abdulhadi Aljawish,Aziza A. El-Nekeety,Sekena H. Abdel-Aziem,Nabila S. Hassan | | Food and Chemical Toxicology. 2017; 99: 209 | | [Pubmed] | [DOI] | | | 14 |
Sirtuin-Activating Compounds (STACs) Alleviate D-Galactosamine/Lipopolysaccharide-Induced Hepatotoxicity in Rats: Involvement of Sirtuin 1 and Heme Oxygenase 1 |
|
| M. K. KEMELO, N. KUTINOVÁ CANOVÁ, A. HORINEK, H. FARGHALI | | Physiological Research. 2017; : 497 | | [Pubmed] | [DOI] | | | 15 |
Hepatoprotective Effect of Quercetin Pretreatment Against Paracetamol-Induced Liver Damage and Partial Hepatectomy in Rats |
|
| Pedro Paulo Barros,Gustavo Henrique da Silva,Gisele Mara Silva Gonçalves,Jessica Cristiane Oliveira,Livia Gonçalves Pagnan,Luiza Arco-e-Flexa | | Brazilian Archives of Biology and Technology. 2017; 60(0) | | [Pubmed] | [DOI] | | | 16 |
A Comparison of the Effects of Quercetin Hydrate With Those of Vitamin E on the Levels of IL-13, PDGF, TNF-a, and INF-? in Bleomycin-Induced Pulmonary Fibrosis in Rats |
|
| Ali Reza Malayeri,Ali Asghar Hemmati,Ardeshir Arzi,Annahita Rezaie,Mehri Ghafurian-Boroojerdnia,Hamid Reza Khalili | | Jundishapur Journal of Natural Pharmaceutical Products. 2016; In press(In press) | | [Pubmed] | [DOI] | | | 17 |
Protective effects of quercetin on thioacetamide-induced acute liver damage and its related biochemical and pathological alterations |
|
| Soheil Ashkani-Esfahani, Fereshteh Bagheri, Negar Azarpira, Elmira Esmaeilzadeh, Yasaman Emami, Nazila Hassanabadi, Marzieh Keshtkar | | The Egyptian Journal of Internal Medicine. 2016; 28(3): 123 | | [Pubmed] | [DOI] | | | 18 |
Hepatoprotective effect of quercetin: From chemistry to medicine |
|
| Selvaraj Miltonprabu,Michal Tomczyk,Krystyna Skalicka-Wozniak,Luca Rastrelli,Maria Daglia,Seyed Fazel Nabavi,Seyed Moayed Alavian,Seyed Mohammad Nabavi | | Food and Chemical Toxicology. 2016; | | [Pubmed] | [DOI] | | | 19 |
Hepato- and neuro-protective effects of watermelon juice on acute ethanol-induced oxidative stress in rats |
|
| Omolola R. Oyenihi,Blessing A. Afolabi,Ayodeji B. Oyenihi,Olusegun J. Ogunmokun,Oluwafemi O. Oguntibeju | | Toxicology Reports. 2016; 3: 288 | | [Pubmed] | [DOI] | | | 20 |
Molecular mechanisms of action of quercetin in cancer: recent advances |
|
| Dharambir Kashyap,Sonam Mittal,Katrin Sak,Paavan Singhal,Hardeep Singh Tuli | | Tumor Biology. 2016; | | [Pubmed] | [DOI] | | | 21 |
Quercetin modulates iNOS, eNOS and NOSTRIN expressions and attenuates oxidative stress in warm hepatic ischemia-reperfusion injury in rats |
|
| Mohamed Abd-Elbaset,El-Shaimaa A. Arafa,Gamal A. El Sherbiny,Mohamed S. Abdel-Bakky,Abdel Nasser A.M. Elgendy | | Beni-Suef University Journal of Basic and Applied Sciences. 2015; 4(3): 246 | | [Pubmed] | [DOI] | | | 22 |
Transgenic flax overexpressing polyphenols as a potential anti-inflammatory dietary agent |
|
| Magdalena Matusiewicz,Iwona Kosieradzka,Malgorzata Sobczak-Filipiak,Magdalena Zuk,Jan Szopa | | Journal of Functional Foods. 2015; 14: 299 | | [Pubmed] | [DOI] | | | 23 |
Flos Albiziae aqueous extract and its active constituent quercetin potentiate the hypnotic effect of pentobarbital via the serotonergic system |
|
| Meng-Fei Ye,Zheng Liu,Shu-Fang Lou,Zhen-Yong Chen,Ai-Yue Yu,Chun-Yan Liu,Chao-Yang Yu,Hua-Fang Zhang,Jian Zhang | | Biomedical Reports. 2015; | | [Pubmed] | [DOI] | | | 24 |
Protective effects of Semen Crotonis Pulveratum on trinitrobenzene sulphonic acid-induced colitis in rats and H2O2-induced intestinal cell apoptosis in vitro |
|
| Xiaohong Wang,Jie Zhao,Zhe Han,Fang Tang | | International Journal of Molecular Medicine. 2015; | | [Pubmed] | [DOI] | | | 25 |
Significance of Rumex Vesicarius as Anticancer Remedy Against Hepatocellular Carcinoma: a Proposal-Based on Experimental Animal Studies |
|
| Abdelaaty A Shahat,Mansour S Alsaid,Soheir E Kotob,Hanaa H Ahmed | | Asian Pacific Journal of Cancer Prevention. 2015; 16(10): 4303 | | [Pubmed] | [DOI] | | | 26 |
Phytoextract of Indian mustard seeds acts by suppressing the generation of ROS against acetaminophen-induced hepatotoxicity in HepG2 cells |
|
| Harita Parikh,Nancy Pandita,Aparna Khanna | | Pharmaceutical Biology. 2015; 53(7): 975 | | [Pubmed] | [DOI] | | | 27 |
Quercetin inhibits the cytotoxicity and oxidative stress in liver of rats fed aflatoxin-contaminated diet |
|
| Aziza A. El-Nekeety,Sekena H. Abdel-Azeim,Aziza M. Hassan,Nabila S. Hassan,Soher E. Aly,Mosaad A. Abdel-Wahhab | | Toxicology Reports. 2014; 1: 319 | | [Pubmed] | [DOI] | | | 28 |
Alcohol use disorders and current pharmacological therapies: the role of GABAA receptors |
|
| Jing Liang,Richard W Olsen | | Acta Pharmacologica Sinica. 2014; 35(8): 981 | | [Pubmed] | [DOI] | | | 29 |
Antioxidant and Prophylactic Effects of Delonix elata L., Stem Bark Extracts, and Flavonoid Isolated Quercetin against Carbon Tetrachloride-Induced Hepatotoxicity in Rats |
|
| Pradeepa Krishnappa,Krishna Venkatarangaiah,Krishna Venkatesh,Santosh Kumar Shivamogga Rajanna,Rajesh Kashi Prakash Gupta | | BioMed Research International. 2014; 2014: 1 | | [Pubmed] | [DOI] | | | 30 |
Quercetin attenuates chronic ethanol hepatotoxicity: Implication of “free” iron uptake and release |
|
| Yuhan Tang,Yanyan Li,Haiyan Yu,Chao Gao,Liang Liu,Mingyou Xing,Liegang Liu,Ping Yao | | Food and Chemical Toxicology. 2014; 67: 131 | | [Pubmed] | [DOI] | | | 31 |
Hepatoprotective effects and antioxidant, antityrosinase activities of phloretin and phloretin isonicotinyl hydrazone |
|
| Ai-Ren Zuo,Yan-Ying Yu,Qing-Long Shu,Li-Xiang Zheng,Xiao-Min Wang,Shu-Hong Peng,Yan-Fei Xie,Shu-Wen Cao | | Journal of the Chinese Medical Association. 2014; | | [Pubmed] | [DOI] | | | 32 |
The protective effects of the combination of sodium ferulate and oxymatrine on ethanol-induced liver damage in mice |
|
| Xiaokun Pei,Wei Wang,Ningshu Miao,Mengxin Xu,Chunlei Zhang,Mengmeng Sun,Mingbo Xu,Zhifeng Liu | | Environmental Toxicology and Pharmacology. 2014; 37(1): 423 | | [Pubmed] | [DOI] | | | 33 |
Vipera russellivenom-induced oxidative stress and hematological alterations: Amelioration by crocin a dietary colorant |
|
| M. Sebastin Santhosh,M. Hemshekhar,R. M. Thushara,S. Devaraja,K. Kemparaju,K. S. Girish | | Cell Biochemistry and Function. 2013; 31(1): 41 | | [Pubmed] | [DOI] | | | 34 |
Quercetin suppressed CYP2E1-dependent ethanol hepatotoxicity via depleting heme pool and releasing CO |
|
| Tang, Y. and Tian, H. and Shi, Y. and Gao, C. and Xing, M. and Yang, W. and Bao, W. and Wang, D. and Liu, L. and Yao, P. | | Phytomedicine. 2013; 20(8-9): 699-704 | | [Pubmed] | | | 35 |
Narirutin fraction from citrus peels attenuates alcoholic liver disease in mice |
|
| Park, H.-Y. and Ha, S.K. and Eom, H. and Choi, I. | | Food and Chemical Toxicology. 2013; 55: 637-644 | | [Pubmed] | | | 36 |
Evaluation of the protective effects of quercetin in biliary cirrhotic rats |
|
| Derakhshanian, H. and Hossein Marjanmehr, S. and Ghadbeigi, S. and Rahimi, N. and Mostafavi, S.A. and Hosseinzadeh, P. and Salehpour, A. and Dehpour, A.R. | | Tehran University Medical Journal. 2013; 71(1): 1-6 | | [Pubmed] | | | 37 |
Vipera russelli venom-induced oxidative stress and hematological alterations: Amelioration by crocin a dietary colorant |
|
| Sebastin Santhosh, M. and Hemshekhar, M. and Thushara, R.M. and Devaraja, S. and Kemparaju, K. and Girish, K.S. | | Cell Biochemistry and Function. 2013; 31(1): 41-50 | | [Pubmed] | | | 38 |
Narirutin fraction from citrus peels attenuates alcoholic liver disease in mice |
|
| Ho-Young Park,Sang Keun Ha,Hyojin Eom,Inwook Choi | | Food and Chemical Toxicology. 2013; 55: 637 | | [Pubmed] | [DOI] | | | 39 |
Quercetin suppressed CYP2E1-dependent ethanol hepatotoxicity via depleting heme pool and releasing CO |
|
| Yuhan Tang,Hongtao Tian,Yanru Shi,Chao Gao,Mingyou Xing,Wei Yang,Wei Bao,Di Wang,Liegang Liu,Ping Yao | | Phytomedicine. 2013; 20(8-9): 699 | | [Pubmed] | [DOI] | | | 40 |
Quercetin Inhibits Left Ventricular Hypertrophy in Spontaneously Hypertensive Rats and Inhibits Angiotensin II-Induced H9C2 Cells Hypertrophy by Enhancing PPAR-? Expression and Suppressing AP-1 Activity |
|
| Lei Yan,Ji Dong Zhang,Bo Wang,Yi Jing Lv,Hong Jiang,Gui Lin Liu,Yun Qiao,Ming Ren,Xue Feng Guo,Lynette Kay Rogers | | PLoS ONE. 2013; 8(9): e72548 | | [Pubmed] | [DOI] | | | 41 |
Dietary agents in the prevention of alcohol-induced hepatotoxicty: preclinical observations |
|
| Arnadi Ramachandrayya Shivashankara,Aysha Azmidah,Raghavendra Haniadka,Manoj Ponadka Rai,Rajesh Arora,Manjeshwar Shrinath Baliga | | Food & Function. 2012; 3(2): 101 | | [Pubmed] | [DOI] | | | 42 |
Wu-Chia-Pi solution attenuates carbon tetrachloride-induced hepatic injury through the antioxidative abilities of its components acteoside and quercetin |
|
| Huan, S.K.-H. and Wang, K.-T. and Lee, C.-J. and Sung, C.-H. and Chien, T.-Y. and Wang, C.-C. | | Molecules. 2012; 17(12): 14673-14684 | | [Pubmed] | | | 43 |
Quercetin prevents ethanol-induced dyslipidemia and mitochondrial oxidative damage |
|
| Tang, Y. and Gao, C. and Xing, M. and Li, Y. and Zhu, L. and Wang, D. and Yang, X. and Liu, L. and Yao, P. | | Food and Chemical Toxicology. 2012; 50(5): 1194-1200 | | [Pubmed] | | | 44 |
S-allylmercaptocysteine reduces carbon tetrachloride-induced hepatic oxidative stress and necroinflammation via nuclear factor kappa B-dependent pathways in mice |
|
| Xiao, J. and Liong, E.C. and Ling, M.-T. and Ching, Y.-P. and Fung, M.-L. and Tipoe, G.L. | | European Journal of Nutrition. 2012; 51(3): 323-333 | | [Pubmed] | | | 45 |
Dietary agents in the prevention of alcohol-induced hepatotoxicty: Preclinical observations |
|
| Shivashankara, A.R. and Azmidah, A. and Haniadka, R. and Rai, M.P. and Arora, R. and Baliga, M.S. | | Food and Function. 2012; 3(2): 101-109 | | [Pubmed] | | | 46 |
S-allylmercaptocysteine reduces carbon tetrachloride-induced hepatic oxidative stress and necroinflammation via nuclear factor kappa B-dependent pathways in mice |
|
| Jia Xiao,Emily C. Liong,Ming-Tat Ling,Yick-Pang Ching,Man-Lung Fung,George L. Tipoe | | European Journal of Nutrition. 2012; 51(3): 323 | | [Pubmed] | [DOI] | | | 47 |
Quercetin prevents ethanol-induced dyslipidemia and mitochondrial oxidative damage |
|
| Yuhan Tang,Chao Gao,Mingyou Xing,Yanyan Li,Liping Zhu,Di Wang,Xuefeng Yang,Liegang Liu,Ping Yao | | Food and Chemical Toxicology. 2012; 50(5): 1194 | | [Pubmed] | [DOI] | | | 48 |
Protective effect of aqueous extract of the rhizomes of Sansevieria liberica gérôme and labroy on carbon tetrachloride induced hepatotoxicity in rats |
|
| Ikewuchi, J.C. and Ikewuchi, C.C. and Igboh, N.M. and Mark-Balm, T. | | EXCLI Journal. 2011; 10: 312-321 | | [Pubmed] | | | 49 |
Hepatoprotective effect of aqueous extract of Aframomum melegueta on ethanol-induced toxicity in rats |
|
| Nwozo, S.O. and Oyinloye, B.E. | | Acta Biochimica Polonica. 2011; 58(3): 355-358 | | [Pubmed] | | | 50 |
Protective effect of sodium aescinate on lung injury induced by methyl parathion |
|
| Du, Y. and Wang, T. and Jiang, N. and Ren, R.-T. and Zhao, D.-L. and Li, C. and Fu, F.-H. | | Human and Experimental Toxicology. 2011; 30(10): 1584-1591 | | [Pubmed] | | | 51 |
Protective effect of sodium aescinate on lung injury induced by methyl parathion |
|
| Yuan Du,Tian Wang,Na Jiang,Ru-Tong Ren,De-Lu Zhao,Chong Li,Feng-Hua Fu | | Human & Experimental Toxicology. 2011; 30(10): 1584 | | [Pubmed] | [DOI] | | | 52 |
Catechin Suppresses an Array of Signalling Molecules and Modulates Alcohol-Induced Endotoxin Mediated Liver Injury in a Rat Model |
|
| Sushma Bharrhan,Ashwani Koul,Kanwaljit Chopra,Praveen Rishi,Terence Lee | | PLoS ONE. 2011; 6(6): e20635 | | [Pubmed] | [DOI] | | | 53 |
Catechin suppresses an array of signalling molecules and modulates alcohol-induced endotoxin mediated liver injury in a rat model |
|
| Bharrhan, S., Koul, A., Chopra, K., Rishi, P. | | PLoS ONE. 2010; 6(6): art-e20635 | | [Pubmed] | |
|
 |
|
|
|
