Abstract
Nonalcoholic steatohepatitis (NASH) is characterized by diffuse fatty infiltration in the liver and ballooning degeneration and inflammation in hepatocytes. We aimed to study the protective effect of soy isoflavones on experimental NASH and their effects on plasma paraoxanese and arylesterase levels in rats. Twenty-eight male rats were divided into four groups: Group 1 (n=7) received an isocaloric normal diet for 8 weeks, Group 2 (n=7) was fed an isocaloric basal diet plus oral soy isoflavone for 8 weeks (100 mg/kg in diet), Group 3 (n=7) received a special diet that was methionine and choline deficient (MCD) and rich in fat for 8 weeks, and Group 4 (n=7) was fed a special diet that was MCD and rich in fat plus oral soy isoflavone for 8 weeks (100 mg/kg in diet). Blood samples were collected to measure plasma malondialdehyde (MDA), paraoxanese, and arylesterase and biochemical parameters. Tissue samples were duly taken for histopathological examination and measurement of tissue MDA levels. Plasma MDA levels were higher in Group 3 than in Groups 1, 2, and 4 (P <0.01, P <0.05, and P <0.05 respectively). Liver tissue MDA levels were also significantly higher in Group 3 compared to Groups 1, 2, and 4 (P <0.001, P <0.001, and P <0.05 respectively). A significant decrease was found in the plasma and liver tissue MDA levels in Group 4 compared to Group 3 (P <0.05 and P <0.05, respectively). The activity levels of plasma paraoxanase and arylesterase were significantly higher in Group 2 than in Groups 1 and 3 (P <0.05 and P <0.01, respectively). Also, the plasma paraoxanase and arylesterase levels were significantly higher in Group 4 compared to Groups 1 and 3 (P <0.05 and P <0.01, respectively). A significant reduction was observed in Group 4 in steatosis, inflammation, necrosis, and fibrosis compared to Group 3 (P <0.05 for each). We conclude that soy isoflavones seem to be effective in preventing liver damage by decreasing lipid peroxidation in the NASH model induced by a MCD diet. They stimulate and increase the activity of the antioxidative paraoxanase enyzme while decreasing the total cholesterol and triglyceride levels.
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References
Diehl AM (1999) Nonalcoholic steatohepatitis. Semin Liver Dis 19(2):221–229
Koteish A, Mae Diehl A (2002) Animal models of steatohepatitis. Best Pract Res Clin Gastroenterol 16(5):679–690
Chitturi S, Farrell GC (2001) Etiopathogenesis of nonalcoholic steatohepatitis. Semin Liver Dis 21(1):27–41
Hensley K, Kotake Y, Sang H, Pye QN, Wallis GL, Kolker LM, Tabatabaie T, Stewart CA, Konishi Y, Nakae D, Floyd RA (2000) Dietary choline restriction causes complex I dysfunction and increased H2O2 generation in liver mitochondria. Carcinogenesis 21(5):983–989
Diehl AM (2000) Cytokine regulation of liver injury and repair. Immunol Rev 174:160–171
Hruszkewycz AM (1998) Evidence for mitochondrial DNA dmage by lipid peroxidation. Biochem Biophys Res Commun 153:191–197
Parola M, Pinzani M, Casini A, Albano E, Poli G, Gentilini A, Gentilini P, Dianzani MU (1993) Stimulation of lipid peroxidation or 4-hydroxynonenal treatment increases procollagen alpha 1 (I) gene expression in human liver fat-storing cells. Biochem Biophys Res Commun 194:1044–1050
George J, Pera N, Phung N, Leclercq I, Yun Hou J, Farrell G (2003) Lipid peroxidation, stellate cell activation and hepatic fibrogenesis in a rat model of chronic steatohepatitis. J Hepatol 39:756–764
Kirsch R, Clarkson V, Shephard EG, Marais DA, Jaffer MA, Woodburne VE, Kirsch RE, de Hall PL (2003) Rodent nutritional model of non-alcoholic steatohepatitis: species, strain and sex difference studies. J Gastroenterol Hepatol 18:1272–1282
Martucci CP, Fishman J (1993) P450 enzymes of estrogen metabolism. Pharmacol Ther 57(2–3):237–257
Kulling SE, Lehmann L, Metzler M (2002) Oxidative metabolism and genotoxic potential of major isoflavone phytoestrogens. J Chromotogr 777:211–218
Anila L, Vijayalakshmi NR (2003) Antioxidant action of flavonoids from Mangifera indica and Emblica officinialis in hypercholesterolmic rats. Food Chem 83:569–574
Choi C, Hyeyeon C, Park J, Song Y (2003) Supressive effects of genistein on oxidative stres and NF kB activation in RAW 264.7 macrophages. Biosci Biotechnol Biochem 67(9)1916–1922
Rice Evans CA, Miller NJ, Bolwell PG, Bramley PM, Pridham JB (1995) The relative antioxidant activities of plant derived polyphenolic flavonoids. Free Radical Res 22:375–383
Abad MJ, Bermejo P, Willar A (1995) The activity of flavonoids extracted from Tnacetum microphylumm DC (Compositae) on soybean lipoxygenase and prostaglandin synthetase. Gen Pharmacol 26:815–819
Robak J, Gryglewsky RJ (1996) Bioactivity of flavonoids. Polish J Pharmacol Pharm 48:555–564
Wiseman H, O'Reilly JD, Adlercreutz H, Mallet AI, Bowey EA, Rowlland IR, Sanders TA (2000) Isoflavone phytoestrogens consumed in soy decrease F (2)-isoprostane concentrations and increase resistance of low-density lipoprotein to oxidation in humans. Am J Clin Nutr 72(2):395–400
Djuric Z, Chen G, Doerge DR, Heilbrun LK, Kucuk O (2001) Effect of soy isoflavone supplementation on markers of oxidative stress in men and women. Cancer Lett 22(1):1–6
Demonty I, Lamrche B, Deshaies Y, Jacques H (2002) Role of soty isoflavones in the hypotrigliseridemic effect of soy protein in the rat. J Nutr Biochem 13:671–677
Beynen AC (1990) Mode of cholesteremic action of dieatary proteins. Monogr Atheroscler 16:153–159
Sanchez A, Hubbard RW (1991) Plasma amino acids and the insulin glucagon ratio as a explanation for the dietary protein modulation of atherosclerosis. Med Hypothesis 36:27–32
Forsyhte WA (1990) Dietary protein, cholesterol and thyroxine: a proposed mechanism. J Clin Nutr 68(Suppl):S101–S104
Potter SM (1998) Soy protein and cardiovascular disease: the impact of bioactive components in soy. Nutr Rev 56:231–235
Rinella ME, Green RM (2004) The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance. J Hepatol 40(1):47–51
Yagi K (1984) Assay for blood plasma and serum. Methods Enzmol 105:328–331
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipide eproxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358
Ruiz J, Blanche H, James RW, Garin MC, Vaisse C, Charpentier G, Cohen N, Morabia A, Passa P, Froguel P (1995) Gln-Arg 192 polymorphysm of paraoxonase and coronary heart disease in y-type 2 diabetes. Lancet 346:869–872
Juretic D, Tadjanovic M, Rekic B, Simeon Rudolf V, Reiner E, Barlicic M (2001) Serum paraoxonase actiivities in hemodialyzed uremic patients. Cohort study Croat Med J 42:146–150
Brunt E, Janney C, Bisceglie A, Neuschwander-Tetri BA, Bacon BR (1999) Nonalcoholic steatohepatitis; a proposal for grading and staging the histopathologic lesions. Am J Gastroenterol 94:2467–2474
Bahcecioglu IH, Yalniz M, Ataseven H, Bulbuller N, Kececi M, Demirdag K, Ozercan I, Ustundag B (2004) TNF-alpha and leptin in experimental liver fibrosis models induced by carbon tetrachloride and by common bile duct ligation. Cell Biochem Funct 22(6):359–363
Kirsch R, Clarkson V, Shephard EG, Marais DA, Jaffer MA, Woodburne VE, Kirsch RE, Hall PL (2003) Rodent nutritional model of non-alcoholic steatohepatitis: species, strain and sex difference studies. J Gastroenterol Hepatol 18(11):1272–1282
Fort J, Oberti F, Pilette C, Veal N, Gallois Y, Douay O, Rousselet MC, Rosenbaum J, Cales P (1998) Antifibrotic and hemodynamic effects of the early and chronic administration of octreotide in two models of liver fibrosis in rats. Hepatology 28(6):1525–1531
Harrison SA, Kadakia S, Lang K, Schenker S (2002) Nonalcoholic steatohepatitis: What we know in the new millenium. Am J Gastroenterol 97:2714–2724
Lee RG (1989) Nonalcoholic steatohepatitis: A study of 39 patients. Hum Pathol 20:594–598
Day C, James O (1998) Steatohepatitis: A tale of two “hits”? Gastroenterology 114:842–845
Lieber CS (1997) Role of oxidative stres and antioxidant therapy in alcoholic and nonalcholic liver disease. Adv Pharmacol 38:601–628
Aviram M (1996) Interaction of oxidized low density lipoproteins and increased atherogenicty of antioxidants. Eur J Clin Chem Clin Biochem 34:599
Zhishen J, Mengencheng T, Jianmibg W (1999) The determination of flavonoid contents in mulberry and their scavenging effects on superoxide radicals. Food Chem 64:555–559
Gryglewski RJ, Korbut R, Robak J, Swies J (1987) On the mechanism of antithrombotic action of flavonoids. Biochem Pharmacol 36(3):317–322
Lee MK, Bok SH, Jeong TS, Moon SS, Lee SE, Park YB, Choi MS (2002) Supplementation of Naringenin and its synthetic derivative alters antioxidant enzyme activities of erythrocyte and liver in high cholesterol fed rats. Biorg Med Chem 10:2239–2244
Seo HJ, Jeong KS, Lee MK, Park YB, Jung UJ, Kim HJ, Choi MS (2003) Role of naringenin suplement in regulation of lipid and ethanol metabolism in rats. Life Sci 73:933–946
Fuhrman B, Aviram M (2001) Flavonoids protect LDL from oxidation and attenuate atherosclerosis. Curr Opin Lipidol 12(1):41–48
Beltowski J, Wojcicka G, Jamroz A (2003) Leptin decreases plasma paroxonase 1 activity and induces oxidative stress: the possible novel mechanism for proatherogenic effect of chronic hyperleptinemia. Atheroclerosis 170:21–29
Beltowski J, Wojcica G, Mydlardrczyk M, Jamroz A (2002) The effect of peroxisome prolifarator activated receptors alpha (PPAR a) agonist fenofibrate on lipid peroxidation, total antioxidant capacity and plasma paraoxonase 1 (PON1) activity. J Physiol Pharmacol 53:463–475
Starkel P, Sempoux C, Leclercq I, Herin M, Deby C, Desager JP, Horsmans Y (2003) Oxidative stress, KLF6 and transforming growth factor-beta up-regulation differentiate non-alcoholic steatohepatitis progressing to fibrosis from uncomplicated steatosis in rats. J Hepatol 39(4):538–546
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Vitamin B12, methionine- and choline-deficient diet, and choline chloride were supplied by Farmövert A.Ş
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Ustundag, B., Bahcecioglu, I.H., Sahin, K. et al. Protective Effect of Soy Isoflavones and Activity Levels of Plasma Paraoxonase and Arylesterase in the Experimental Nonalcoholic Steatohepatitis Model. Dig Dis Sci 52, 2006–2014 (2007). https://doi.org/10.1007/s10620-006-9251-9
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DOI: https://doi.org/10.1007/s10620-006-9251-9