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The hepatoprotective effect of putrescine against cadmium-induced acute liver injury

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Abstract

The hepatoprotective effect of putrescine against cadmium liver injury was investigated. Male Wistar rats were injected with a dose of cadmium (6.5 mg CdCl2/kg bodyweight, intraperitoneally). Normal saline (group I) or putrescine (300 µmol/kg bodyweight; group II) were injected 2, 5 and 8 h later. A number of animals of both groups were killed 0, 12, 16, 24, 48 or 60 h after cadmium intoxication. Liver tissue was histologically assessed for necrosis, apoptosis, peliosis, mitoses, and inflammatory infiltration. Apoptosis was also quantified by the TUNEL assay for hepatocytes and nonparenchymal liver cells. The discrimination between hepatic cell subpopulations was achieved histochemically. The mitotic index in hematoxylin–eosin-stained sections and by the immunochemical detection of Ki67 nuclear antigen, 3H-thymidine incorporation into hepatic DNA, and hepatic thymidine kinase activity were all used as indices of liver regeneration. Both hepatocyte apoptosis and liver necrosis evolved in a biphasic temporal pattern. Nonparenchymal cell apoptosis and peliosis hepatis evolved in a monophasic pattern and were correlated closely. Putrescine administration totally reversed liver necrosis and hepatocyte apoptosis. The time profile of nonparenchymal apoptosis was altered and peliosis hepatis was also totally attenuated. In conclusion, putrescine protected hepatocytes and modulated the mechanism of cadmium-induced acute hepatotoxicity.

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References

  • Ballas SK, Mohandas N, Marton LJ, Shohet SB (1983) Stabilization of erythrocyte membranes by polyamines. Proc Natl Acad Sci USA 80:1942–1946

    CAS  PubMed  Google Scholar 

  • Brune B, Hartzell P, Nicotera P, Orrenius S (1991) Spermine prevents endonuclease activation and apoptosis in thymocytes. Exp Cell Res 195:323–329

    CAS  PubMed  Google Scholar 

  • Casalino E, Sblano C, Landriscina C (1997) Enzyme activity alteration by cadmium administration to rats: the possibility of iron involvement in lipid peroxidation. Arch Biochem Biophys 346:171–179

    Article  CAS  PubMed  Google Scholar 

  • Dong W, Simeonova PP, Gallucci R, Matheson J, Flood L, Wang S, Hubbs A, Luster MI (1998) Toxic metals stimulate inflammatory cytokines in hepatocytes through oxidative stress mechanisms. Toxicol Appl Pharmacol 151:359–366

    Google Scholar 

  • Dudley RE, Svoboda DJ, Klaassen CD (1982) Acute exposure to cadmium causes severe liver injury in rats. Toxicol Appl Pharmacol 65:302–313

    CAS  PubMed  Google Scholar 

  • Dudley RE, Svoboda DJ, Klaassen CD (1984) Time-course of cadmium-induced ultrastructural changes in rat liver. Toxicol Appl Pharmacol 76:150–160

    Google Scholar 

  • Esteve JM, Mompo J, Garcia De La Asuncion J, Sastre J, Asensi M, Boix J, Vina JR, Palladro FV (1999) Oxidative damage to mitochondrial DNA and glutathione oxidation in apoptosis: studies in vivo and in vitro. FASEB J 13:1055–1064

    CAS  PubMed  Google Scholar 

  • Fowler BA (1991) Other toxic effects. In: Friberg L, Elinder CG, Kjellstrom T, Nordberg GF (eds.) Cadmium and health: a toxicological and epidemiological appraisal. CRC Press, Boca Raton FL, pp 159–204

  • Habeebu SS, Liu J, Klaassen CD (1998) Cadmium-induced apoptosis in mouse liver. Toxicol Appl Pharmacol 149:203–209

    CAS  PubMed  Google Scholar 

  • Heby O (1981) Role of polyamines in the control of cell proliferation and differentiation. Differentiation 19:1–20

    CAS  PubMed  Google Scholar 

  • Igarashi K, Kashiwagi K (2000) Polyamines: mysterious modulators of cellular functions. Biochem Biophys Res Commun 271:559–564

    Article  CAS  PubMed  Google Scholar 

  • Kahn D, Svanas GW, Eagon PK, Makowka L, Podesta L, Chapchap P, Starzl TE, Van Thiel DH (1988) Effect of an antiandrogenic H2 receptor antagonist on hepatic regeneration in rats. J Lab Clin Med 112:232–239

    CAS  PubMed  Google Scholar 

  • Kayama F, Yoshida T, Elwell MR, Luster MI (1995) Role of tumor necrosis factor-α in cadmium-induced hepatotoxicity. Toxicol Appl Pharmacol 131:224–234

    Google Scholar 

  • Khan AU, Di Mascio P, Medeiros MH, Wilson T (1992) Spermine and spermidine protection of plasmid DNA against single-strand breaks induced by singlet oxygen. Proc Natl Acad Sci USA 89:11428–11430

    CAS  PubMed  Google Scholar 

  • Koizumi T, Yokota T, Shirakura H, Tsatsumoto H, Suzuki KT (1994) Potential mechanism of cadmium-induced cytotoxicity in rat hepatocytes: inhibitory action of cadmium on mitochondrial respiratory activity. Toxicology 92:115–125

    Article  CAS  PubMed  Google Scholar 

  • Koizumi T, Shirakura H, Kumagai H, Tsatsumoto H, Suzuki KT (1996) Mechanism of cadmium-induced cytototoxicity in rat hepatocytes: cadmium-induced active oxygen-related permeability changes of the plasma membrane. Toxicology 114:125–134

    Article  CAS  PubMed  Google Scholar 

  • Kotsonis FN, Klaassen CD (1997) Toxicity and distribution of cadmium administered to rats at sublethal doses. Toxicol Appl Pharmacol 41:667–680

    Google Scholar 

  • Kyprianidis KG, Mykoniatis MG, Papadimitriou DG, Valsamidou A (1996) Effect of subtotal pancreatectomy on the rate of liver regeneration: the role of hepatic stimulator substance. J Surg Res 62:267–272

    Article  CAS  PubMed  Google Scholar 

  • Lowry O, Rosenbrough N, Farr A, Randall R (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193; 265–275

    Google Scholar 

  • Motoyama S, Minamiya Y, Saito S, Saito R, Matsuzaki I, Abo S, Inaba H, Enomoto K, Kitamura M (1998) Hydrogen peroxide derived from hepatocytes induces sinusoidal endothelial cell apoptosis in perfused hypoxic rat liver. Gastroenterology 114:153–163

    Google Scholar 

  • Muller L, Ohnesorge FK (1984) Cadmium-induced alternation of the energy level in isolated hepatocytes. Toxicology 31:297–306

    Article  CAS  PubMed  Google Scholar 

  • Munro HN, Fleck A (1966) Recent developments in the measurement of nucleic acids in biological materials. A supplementary review. Analyst 91:78–88

    CAS  PubMed  Google Scholar 

  • Nagoshi S, Ohta Y, Matsui A, Fujiwara K (1994) Protective action of putrescine against rat liver injury. Scand J Gastroenterol 29:166–171

    CAS  PubMed  Google Scholar 

  • Nishiguchi S, Kuroki T, Nakajima S, Shiomi S, Seki S, Matsui-Yuasa I, Otani S, Kobayashi K (1990) Effects of putrescine on d-galactosamine-induced acute liver failure in rats. Hepatology 12:348–353

    CAS  PubMed  Google Scholar 

  • Ohmori S, Misaizu T, Kitada M, Kitagawa H, Igarashi K, Hirose S, Kanakubo Y (1988) Polyamine lowered the hepatic lipid peroxide level in rats. Res Commun Chem Pathol Pharmacol 62:235–249

    CAS  PubMed  Google Scholar 

  • Pasternak K (1997) The effectiveness of the bonding of amino acid by tRNA of livers of rats experimentally exposed to cadmium and barium. Ann Univ Mariae Curie Sklodowska 52:161–165

    CAS  Google Scholar 

  • Richards G (1974) Modifications of the diphenylamine reaction giving increased sensitivity and simplicity in the estimation of DNA. Anal Biochem 57:369–376

    CAS  PubMed  Google Scholar 

  • Rikans LE, Yamano T (2000) Mechanisms of cadmium mediated-acute hepatotoxicity. J Biochem Mol Toxicol 14:110–117

    Article  CAS  PubMed  Google Scholar 

  • Sakagami H, Fujiwara E, Yokote Y, Akahane K, Asano K, Kochi M, Hara E, Shirahata A (2000) Changes in intracellular concentrations of amino acids and polyamines during the apoptosis of HL-60 cells. Anticancer Res 20:265–270

    CAS  PubMed  Google Scholar 

  • Saplakoglu U, Iscan M, Iscan M (1997) DNA single-strand breakage in rat lung, liver and kidney after single and combined treatments of nickel and cadmium. Mutat Res 394:133–140

    Article  CAS  PubMed  Google Scholar 

  • Schuber F (1989) Influence of polyamines on membrane functions. Biochem J 260:1–10

    CAS  PubMed  Google Scholar 

  • Simpkins CO, Zhao HL, Gebrehiwot R, Tyndall JA, Torrence CA, Fonong T, Balderman S, Mensah E, Sokolove PM (1996) Opposite effects of metallothionein I and spermine on mitochondrial function. Life Sci 58:2091–2099

    Article  CAS  PubMed  Google Scholar 

  • Tabor CW, Tabor H (1984) Polyamines. Annu Rev Biochem 53:749–790

    PubMed  Google Scholar 

  • Tadolini B, Cabrini L, Landi L, Varani E, Pasquali P (1984) Polyamine binding to phospholipid vesicles and inhibition of lipid peroxidation. Biochem Biophys Res Commun 122:550–555

    CAS  PubMed  Google Scholar 

  • Tzirogiannis CN, Panoutsopoulos GI, Demonakou MD, Hereti RI, Alexandropoulou KN, Basayannis AC, Mykoniatis MG (2003) Time course of cadmium-induced acute hepatotoxicity in the rat liver: the role of apoptosis. Arch Toxicol 77:694–701

    Article  CAS  PubMed  Google Scholar 

  • Tzirogiannis CN, Panoutsopoulos GI, Demonakou MD, Hereti RI, Alexandropoulou KN, Mykoniatis MG (2004) Effect of hepatic stimulator substance (HSS) on cadmium-induced acute hepatotoxicity in the rat liver. Dig Dis Sci (in press)

  • Yamano T, Shimizu M, Noda T (1998) Age-related change in cadmium-induced hepatotoxicity in wistar rats: role of Kupffer cells and neutrophils. Toxicol Appl Pharmacol 151:9–15

    Google Scholar 

  • Yamano T, De Cicco LA, Rikans LE (2000) Attenuation of cadmium-induced liver injury in senescent male Fischer 344 rats: role of Kupffer cells and inflammatory cytokines. Toxicol Appl Pharmacol 162:68–75

    Google Scholar 

  • Yanagawa K, Yamashita T, Yada K, Ohira M, Ishikawa T, Yano Y, Otani S, Sowa M (1998) The antiproliferative effect of HGF on hepatoma cells involves induction of apoptosis with increase in intracellular polyamine concentration levels. Oncol Rep 5:185–190

    CAS  PubMed  Google Scholar 

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Correspondence to Georgios I. Panoutsopoulos.

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Tzirogiannis, K.N., Panoutsopoulos, G.I., Demonakou, M.D. et al. The hepatoprotective effect of putrescine against cadmium-induced acute liver injury. Arch Toxicol 78, 321–329 (2004). https://doi.org/10.1007/s00204-004-0549-0

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