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INT. J. IMMUNOTHERAPY XIX(2-4) 129-134 (2003) PROTECTIVE EFFECT OF UKRAIN AGAINST ACUTE ACETAMINOPHEN- LEVINA O.A.,1 GONCHAROVA I.A.,2 FILATOVA T.G.,1 NADEEV A.P.,3 NOWICKY W.,4 SUKHENKO T.G.,5 KOLESNIKOVA O.P.,5 KOROLENKO T.A.1 1) Laboratory of Cellular Biochemistry, Institute of Physiology, Russian Academy of Medical Sciences, 2) First Hospital of Municipal Infectious Diseases, Novosibirsk, Russia.
3) Novosibirsk Medical Academy, Novosibirsk, Russia.
4) Ukrainian Anti-Cancer Institute, Vienna, Austria.
5) Institute of Clinical and Experimental Immunology, Russian Academy of Medical Sciences, Novosibirsk, Summary: A high dose of acetaminophen (AAP; 1000 mg/kg, single, p.o) administered to rats induced acuteliver failure with centrolobular degeneration and necrosis. We studied the role of hepatic macrophages (Kupffercells) in the modulation of the acetaminophen-induced damage to the liver. Ukrain, which is known to possessimmunomodulatory characteristics, has been shown to exhibit a positive hepatoprotective effect in human viralhepatitis C, significantly preventing liver cell injury. The selective inhibitor of Kupffer cells, gadolinium chloride(GdCl , 7.5 mg/kg i.v., administered 24 h before AAP), and the macrophage stimulator carboxymethylated (1→ 3)- mg/kg i.p., administered 48 h before AAP), were used to modulate the activity of liver macrophages. It was shown that preliminary administration of Ukrain, CMG or GdCl to rats produced in each normalizing liver functional tests and reducing damage to the liver. The role of tumor necrosis factor (TNF)-alpha secretion in the protective effect of these agents in AAP-induced hepatitis is dis-cussed.
Address for correspondence: T.A. Korolenko, Laboratory ofCellular Biochemistry, Institute of Physiology, Russian Ukrain has been shown to exhibit a significant Academy of Medical Sciences, 4 Timakov Street, Novosi-birsk 630117, Russia.
hepatoprotective effect in human viral hepatitis C, Tel: +7 383 233 4872 Fax: +7 383 232 4254 preventing liver cell injury (1-3). We suggested that Ukrain could prevent liver damage in other types of hepatitis, in particular those induced by drugs that 24 h after AAP administration (group 2). Ukrain was have side effects on liver structure and function. injected at a dose of 2 mg/kg i.v. to intact rats (group Acetaminophen (AAP) is a well known medical 3), or 48 h prior to administration of AAP (group 6).
drug, widely used in the therapy of numerous inflam- CMG was administered at a dose of 25 mg/kg i.p. to matory diseases (4-6). It has been shown that high intact rats (group 4), or 48 h prior to administration of doses of AAP can induce toxic hepatitis and liver fail- AAP (group 7); GdCl was administered in the tail ure in humans and experimental animals, accompa- vein at a dose of 7.5 mg/kg to intact rats (group 5), or nied by the development of centrolobular necrosis 24 h prior to administration of AAP (group 8).
(6-8). It has been suggested that AAP toxicity is theresult of the interaction of its metabolite N-acetyl-p- Liver functional tests. Functional assays of serum benzoquinone with liver proteins and of the depletion transaminase activity (alanine transaminase [ALT], of glutathione in liver cells (8). In this study, we tested aspartate transaminase [AST]) were carried out using the hypothesis that the functional activity of liver non- a Cobas Mira biochemical analyzer (Cobas Mira La parenchymal cells (macrophages, endothelial cells) Roche Diagnostic System, Basel, Switzerland) and Bio- can play an important role in the development of toxic con Diagnostik kits (Biocon Diagnostik GmbH, Vöhl- hepatitis induced by high doses of AAP (4, 7, 9-11).
Marienhagen, Germany). The activity of enzymes wasexpressed in U/L. TNF-alpha. TNF-alpha level was measured in the supernatant of peritoneal macrophages by the bio-logical method according to Flick (12), using the Study design. Male Wistar rats weighing 200-250 g TNF-alpha sensitive cell line L-929 purchased from the (Institute of Cytology and Genetics, Russian Academy Russian Ministry of Public Health State Research Center of Sciences, Novosibirsk, Russia) were used. Rats were for Virology and Biotechnology ‘Vector’ (Koltsovo, Rus- with Ukrain (Nowicky Pharma, Austria) at a sia). For the standard curve, murine recombinant TNF- dose of 2 mg/kg i.v. administered 48 h before admin- alpha was used, the results being expressed in pg/ml.
istration of AAP. As positive and negative controls ofmacrophage stimulation, water-soluble carboxymeth- Light microscopy study of the liver. For the prepa- ylated (13)-beta-D-glucan (CMG; Institute of Chemis- ration of histological samples, livers were removed try, Slovak Academy of Sciences, Bratislava, Slovakia) and fixed in 10% buffered formalin (ALTEY Labor- at a dose of 25 mg/kg i.p. 48 h before administration atory, Moscow, Russia) and paraffin-embedded sec- of AAP, and a macrophage activity suppressing agent, tions were stained with hematoxylin-eosin (ALTEY gadolinium chloride (GdCl ; kind gift of Prof. Hardonk, Laboratory). Statistical analysis of the results was Department of Pharmacokinetics and Drug Delivery, carried out on Statistica for Windows (release 5.1 A, University of Groningen, The Netherlands) at a dose 1984-1996, Tulsa, OK, USA), using Student’s t-test; of 7.5 mg/kg i.v. 24 h before administration of AAP, values were considered as significant at p < 0.05.
As control, intact rats were used (group 1). Toxic hepatitis was induced by AAP (ICN Biomedicals,Irvine, CA, USA) administered to the rats in a single TNF-alpha production by isolated peritoneal macro- dose of 1,000 mg/kg p.o. (7); animals were sacrificed phages. In the first series of experiments it was re- Protective effect of Ukrain against acute acetaminofen-induced hepatitis in rats vealed that CMG (25 mg/kg, single dose) increased animals with AAP hepatitis, preliminary administra- TNF-alpha production by isolated peritoneal macro- tion of the immunomodulator Ukrain or the macro- phages. The TNF-alpha level in the macrophage phage stimulator CMG prevented the development of supernatant of intact animals was 333 ± 30 pg/ml.
centrolobular necrosis and the dystrophy of hepato- Following CMG administration this increased to 831 ± 80 pg/ml. The value in the positive control group inthis part of study after treatment with zymosan Serum ALT and AST activity. Serum ALT and AST (Sigma, St. Louis, MO, USA), a known macrophage activity was studied in rats with AAP-induced hepati- stimulator, at a dose of 100 mg/kg i.p. 6 h after tis and in the groups receiving a combined adminis- administration of CMG, was 1,560 ± 200 pg/ml. This tration of AAP and the macrophage function modula- showed that CMG-induced macrophage stimulation tor. The treatment of the rats with AAP resulted in a was followed by increased TNF-alpha production, 10- to 13-fold increase in serum ALT and AST activi- but the effect was less than that of the macrophage ty, indicating the development of cytolytic syndrome and damage to liver cells (Table II). The elevation ofALT and AST activity was significantly reduced by Liver weight. Liver weight increased in the AAP pretreatment with Ukrain and CMG (Table II). Ad- hepatitis group and in the AAP groups receiving pre- ministration of Ukrain or CMG alone to intact rats had liminary administration of Ukrain or CMG. There were no effect on serum transaminase activity. Positive, no changes in spleen weight in any group studied but less significant, effects were observed in rats with Light microscopic study of the liver. AAP adminis- White blood cells. It was shown that AAP de- Table I Effect of Ukrain, during acetaminophen creased the total number of white blood cells com- acute toxic hepatitis with centrolobular necroses.
pared with the control animals (Table III). CMG ad- Vacuolar dystrophy occurred in some hepatocytes, ministration to intact animals was followed by relative and proliferation of sinusoidal cells was observed. In neutropenia and a slight tendency to lymphocytosis.
carboxymethylated (13)-beta-D-glucan (CMG) and gadolinium chloride (GdCl ) treatment on rat liver and spleen weight Liver weight (g)Relative liver weight (g) Table II Effect of Ukrain, carboxymethylated (13)-beta-D-glucan (CMG) and gadolinium chloride (GdCl ) treatment on the serum alanine transaminase (ALT) and aspartate transaminase (AST) activity of rats with acetaminophen (AAP)-induced hepatitis There was also a tendency to neutropenia in the case kines), among which the most important are TNF- of administration of Ukrain to intact rats (Table III).
alpha, interleukin (IL)-6 and IL-8 (9, 10, 13). Cytokines Combined administration of Ukrain and AAP pro- induce the neutrophils to release the biologically duced no changes in white blood cell count or differ- active substances—H O , free oxygen radicals and ential count as compared with intact rats, nor were polymorphonuclear cell elastase—with a simultane- there any changes in these indexes in the groups re- ous decrease in peroxisomal catalase activity in liver ceiving CMG with AAP and GdCl with AAP (Table III). cells (5, 14). This is probably why preliminary appli- cation of the known peroxisome activator clofibrate,resulting in a decrease in H O synthesis, consider- ably reduced toxic damage to the liver by AAP (15).
At 24 h after its administration, AAP administered Table III Effects differential count Page Proofs known that inflammation is followed by the to rats at a dose of 1,000 mg/kg leads to acute liver secretion of primary inflammatory mediators (cyto- failure accompanied by centrolobular degeneration of gadolinium chloride (GdCl ), carboxymethylated (13)-beta-D-glucan (CMG) and Ukrain on the white blood cell (WBC) and in rats with acetaminophen (AAP)-induced hepatitis PMN: polymorphonuclear leucocyte; * percent of total leucocytes; **p < 0.05, compared to control. Protective effect of Ukrain against acute acetaminofen-induced hepatitis in rats and necrosis, with a considerable increase in serum and IL-6 by macrophages, reducing their participa- transaminase activity (ALT and AST). The pretreat- tion in the inflammatory process (6). GdCl both ment of rats with the immunomodulator Ukrain, the selectively depletes the population of large macro- macrophage stimulator CMG and the selective in- phages in the liver, and decreases nitric oxide pro- hibitor of liver macrophages GdCl , prevented in each duction and the formation of peroxide oxidation prod- case the development of AAP-induced hepatitis, nor- ucts (4). It appears that the mechanism of protective malizing functional and structural changes to liver cells.
action in AAP hepatitis of the various compounds Changes in TNF-alpha secretion by macrophages studied is connected with the secretory activity of due to CMG can modify the degree of liver injury macrophages and requires further analysis.
caused by hepatotropic agents. Ukrain was shown toexhibit a hepatoprotective effect in experimentalhepatitis, and may be useful in the treatment of drug- We found that in acute toxic hepatitis induced by (1) Boyko V.N., Belskiy S.N. The influence of the novel drug Ukrain on hemo- and immunopoiesis at the time of its maximum AAP, Ukrain and CMG each had a protective effect via radioprotective effect. Drugs Exp. Clin. Res., 24(5/6), 335, 1998.
the stimulation of liver macrophages (with increased (2) Voltchek I., Sologub T., Nowicky J.W., et al. Preliminary TNF-alpha production in isolated macrophages in results of individual therapy of chronic hepatitis C by Ukrain and inter- the case of CMG), while the protective effect of GdCl feron-alpha. Drugs Exp. Clin. Res., 26(5/6), 261, 2000.
was via the suppression of liver macrophages.
(3) Zhalilo L.I., Susak Y.M., Zemskov S.V., Susak I.A. Influence of Ukrain on the redox processes of hepatocyte. Drugs Exp. Clin. Res., According to previous results, preliminary stimulation of liver macrophages by lipopolysaccharide (LPS) (4) Michael S.L., Pumford N.R., Niesman M.R., Hinson J.A.
has a protective effect in toxic liver injury (7). A posi- Pretreatment of mice with macrophage inactivators decreases aceta- tive effect from macrophage stimulation was also minophen hepatotoxicity and the formation of reactive oxygen and nitrogen species. Hepatology, 30(1), 186, 1999.
(5) Mirochnichenko O., Neisborot-Lefkowitz M., Yang C., Inouye acute blood loss. It is probable that previously primed M. Acetaminophen toxicity. Opposite effects of two forms of gluta- macrophages are not able to secrete significant tione peroxidase. J. Biol. Chem., 274(15), 10349, 1999.
amounts of cytokines, and as a result such macro- (6) Vengerobskii A.I., Saratikov A.S. The mechanisms of the phages are less involved in the development of toxic hepatotoxicity of paracetamol. Farmakol. Toxicol., 54(1), 76, 1991.
(7) Laskin D.L., Gardner C.R., Price V.F., Jollow D.J. Modulation of macrophage functioning abrogates the acute hepatotoxicity of The protective effect of Ukrain in experimental acetaminophen. Hepatology, 21(4), 1045, 1985.
AAP hepatitis opens up the possibility of its use in the (8) Matthews A.M., Roberts D.W., Hinson J.A., Pumford N.R.
treatment of hepatitis induced as a side effect by Acetaminophen-induced hepatotoxicity. Drug Metab. Dispos., some medical drugs. There is a significant possibility (9) Ivashkin V.T. Cellular and molecular biology of liver inflamma- that Ukrain may exhibit a hepatoprotective effect in tion. Rus. J. Gastroent. Hepat. Coloproct., 14(5), 13, 1998 (in human viral hepatitis C, especially in cases of drug- (10) Hinson J.A., Michael S.L., Ault S.G., Pumford N.R. Western We also observed a protective effect of GdCl blot analysis of nitrotyrosine protein addicts in livers of saline-treated against experimental AAP hepatitis, depressing liver and acetaminophen-treated mice. Toxicol. Sci., 53(2), 467, 2000.
(11) Shiratory Y., Hongo S., Hikuba Y., Omata M., et al. Role of macrophages in vivo (17). It is known that GdCl ad- macrophages in regeneration of liver. Dig. Dis. Sci., 41(10), 1939, ministration to rats decreases secretion of TNF-alpha (12) Flick D.A., Gifford G.E. Comparison of in vitro cell cytotoxic (15) Nickolls-Grzemski F.A., Calder I.C., Priestly B.C., Burchan assays for tumor necrosis factor. J. Immunol. Methods, 68, 167, P.C. Clofibrate-induced in vitro hepatoprotection against aceta- minophen is not due to altered glutathione homeostasis. Toxicol.
(13) De Leve L.D., Wang X., Kaplowitz N., Van der Hoek A.
Sinusoidal endothelial cells as target for acetaminophen. Direct (16) Korolenko T.A., Poteryaeva O.N., Li X., Uchkina T.V. Acute phase proteins as biological markers of addictive disorders in action versus requirement for hepatocyte in different mouse strains.
teenagers and children. Int. J. Circumpolar Health, 60, 288, 2001.
Biochem. Pharmacol., 53(9), 1339, 1997.
(17) Hardonk M.J., Dijkhuis F.W., Hulstaert C.E., Koudstaal J.
(14) Lores-Arnaiz S., Lesuy S., Cutrin J.C., Boveris A. Oxidative Heterogeneity of rat liver and spleen macrophages in gadolinium stress by acute acetaminophen administration in mouse liver. Free chloride-induced elimination and repopulation. J. Leukoc. Biol., Radical. Biol. Med., 19(3), 303, 1995.



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