RESUMO
Hepatic glycogen metabolism is altered by nitric oxide (NO) during endotoxic shock. Thalidomide analogs immunomodulate the endotoxin-induced cytokines which regulate the NO release. We analyzed the short-term effects of some thalidomide analogs on the hepatic glycogen store and on the plasma and hepatic NO in an acute model of endotoxic challenge in rat. An endotoxin dose selection was performed. Rats received vehicle, thalidomide or analogs orally and, two hours after last dose, they were injected with endotoxin (5 mg/kg). Animals were sacrificed 2 h after challenge. Liver glycogen was quantified by the anthrone technique. Plasma and hepatic NO was determined by Griess reagent and HPLC. Hepatic interferon-gamma, a NO co-inducer, was measured by ELISA. Endotoxin caused inverse dose-dependent effects on plasma NO and on glycogen.Thalidomide analogs showed short-term regulatory effects on glycogen, some of them increased it. Plasma NO was almost unaffected by analogs but hepatic NO was strikingly modulated. Analogs slightly up-regulated the liver interferon-gamma and two of them increased it significantly. Thalidomide analogs may be used as a pharmacological tool due to their short-term regulatory effects on glycogen and NO during endotoxic shock. Drugs that increase glycogen may improve liver injury in early sepsis.
Assuntos
Endotoxinas/toxicidade , Glicogênio/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Óxido Nítrico/metabolismo , Talidomida/análogos & derivados , Talidomida/farmacologia , Animais , Relação Dose-Resposta a Droga , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Interferon gama/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Óxido Nítrico/sangue , Ratos , Ratos Wistar , Fatores de TempoRESUMO
The effect of oral administration of Rosmarinus officinalis L. (Lamiaceae) on CCl(4)-induced acute liver injury was investigated. Rats were daily treated with the plant extract at a dose of 200 mg/kg corresponding to 6.04 mg/kg of carnosol as determined by reverse phase high-performance liquid chromatography. The treatment was initiated 1 h after CCl(4) administration and Rosmarinus officinalis fully prevented CCl(4) effect on hepatic lipid peroxidation after 24 h of CCl(4) administration. The increase in bilirubin level and alanine aminotransferase activity in plasma induced by CCl(4) was completely normalized by Rosmarinus officinalis. The treatment also produced a significant recovery of CCl(4)-induced decrease in liver glycogen content. CCl(4) did not modify the activity of liver cytosolic glutathione S-transferase (GST) compared with that of control groups. However, Rosmarinus officinalis increased liver cytosolic GST activity and produced an additional increment in plasma GST activity in rats treated with CCl(4). Histological evaluation showed that Rosmarinus officinalis partially prevented CCl(4)-induced inflammation, necrosis and vacuolation. Rosmarinus officinalis might exert a dual effect on CCl(4)-induced acute liver injury, acting as an antioxidant and improving GST-dependent detoxification systems.
Assuntos
Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas , Hepatopatias/tratamento farmacológico , Rosmarinus , Doença Aguda , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Hepatopatias/metabolismo , Masculino , Fitoterapia/métodos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
The aim of this work was to determine if the action mechanism of gadolinium on CCl(4)-induced liver damage is by preventing lipid peroxidation (that may be induced by Kupffer cells) and its effects on liver carbohydrate metabolism. Four groups of rats were treated with CCl(4), CCl(4)+GdCl(3), GdCl(3), and vehicles. CCl(4) was given orally (0.4 g 100 g(-1) body wt.) and GdCl(3) (0.20 g 100 g(-1) body wt.) was administered i.p. All the animals were killed 24 h after treatment with CCl(4) or vehicle. Glycogen and lipid peroxidation were measured in liver. Alkaline phosphatase, gamma-glutamyl transpeptidase, alanine amino transferase activities and bilirubins were measured in rat serum. A liver histological analysis was performed. CCl(4) induced significant elevations on enzyme activities and bilirubins; GdCl(3) completely prevented this effect. Liver lipid peroxidation increased 2.5-fold by CCl(4) treatment; this effect was also prevented by GdCl(3). Glycogen stores were depleted by acute intoxication with CCl(4). However, GdCl(3) did not prevent this effect. The present study shows that Kupffer cells may be responsible for liver damage induced by carbon tetrachloride and that lipid peroxidation is produced or stimulated by Kupffer cells, since their inhibition with GdCl(3) prevented both lipid peroxidation and CCl(4)-induced liver injury.
Assuntos
Gadolínio/farmacologia , Glicogênio/antagonistas & inibidores , Células de Kupffer/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Falência Hepática/metabolismo , Fígado/metabolismo , Alanina Transaminase/sangue , Alanina Transaminase/efeitos dos fármacos , Fosfatase Alcalina/sangue , Fosfatase Alcalina/efeitos dos fármacos , Animais , Bilirrubina/agonistas , Bilirrubina/sangue , Tetracloreto de Carbono , Membrana Celular/enzimologia , Fígado/patologia , Falência Hepática/induzido quimicamente , Masculino , Ratos , Ratos Wistar , gama-Glutamiltransferase/sangue , gama-Glutamiltransferase/efeitos dos fármacosRESUMO
Manganese (Mn) is an essential metal that, in excess, causes an extrapyramidal syndrome consisting in tremor, rigidity and akinesia. Recently, Mn was found to accumulate in brains of cirrhotic patients who also present motor abnormalities. Manganese alters dopaminergic transmission promoting an increase in the turnover of dopamine (DA). In this study, we studied the changes in dopamine and its main metabolite homovanillic acid (HVA) to evaluate DA turnover following administration of manganese to bile-duct obstructed rats. Some groups of rats were treated with manganese chloride in two concentrations: 0.5 and 1 mg/ml of Mn2+ in their drinking water. Four weeks after surgery and treatment with manganese, striatal Mn, DA and HVA were assessed. Marked increases (P<0.05) of striatal manganese content were observed in cirrhotic rats treated and untreated with manganese, these augments were dependent on the Mn concentration in water. Striatal contents of DA in cirrhotic rats diminished by 30% (P<0.05), administration of 0.5 mg/ml of manganese in drinking water to these rats returned dopamine to the basal level and 1 mg/ml of manganese increased dopamine content by 27%. The relationship of Mn content and DA turnover (HVA:DA) in the same animal showed a positive and statically significant correlation (P<0.05), with differences in slope for sham (b1=0.1528) and cirrhotic rats (b1=0.0174). These results suggest that manganese brain accumulation observed in liver failure could be a key element to understand dopamine metabolism in cirrhotic condition of humans.
Assuntos
Dopamina/metabolismo , Fibrose/complicações , Encefalopatia Hepática/complicações , Intoxicação por Manganês/etiologia , Manganês/farmacocinética , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Animais , Bilirrubina/sangue , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Relação Dose-Resposta a Droga , Fibrose/metabolismo , Fibrose/fisiopatologia , Encefalopatia Hepática/enzimologia , Encefalopatia Hepática/fisiopatologia , Ácido Homovanílico/metabolismo , Masculino , Manganês/metabolismo , Intoxicação por Manganês/metabolismo , Intoxicação por Manganês/fisiopatologia , Neostriado/fisiopatologia , Ratos , Ratos WistarRESUMO
Free radicals attack membranes and frequently alter their fluidity and function. The aim of the present work was to study the effect of nitric oxide (NO) radical and peroxynitrite anion on basolateral liver plasma membrane fluidity and on the activity of Na(+)/K(+)-ATPase. Basolateral membranes (BM) were isolated by ultracentrifugation in sucrose gradients and characterized enzymatically. BM were incubated with SNAP (a NO donor) or SIN-1 (a peroxynitrite donor). The release of NO or peroxynitrite was monitored by measuring NO(-)(2) + NO(-)(3). Relative fluidity was measured by polarization of fluorescence. NO increased membrane fluidity while peroxynitrite decreased it in a concentration-dependent manner. Na(+)/K(+)-ATPase activity was reduced by NO or peroxynitrite. Peroxynitrite anion inhibits ATPase activity in part by decreasing fluidity. However, it is very likely that both compounds inhibit ATPase activity by oxidation of the thiol groups of the enzyme. Our results suggest that NO may exert part of its biological effects by modulating membrane fluidity and function.
Assuntos
Fígado/enzimologia , Fluidez de Membrana/efeitos dos fármacos , Molsidomina/análogos & derivados , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Penicilamina/análogos & derivados , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Fracionamento Celular , Polaridade Celular , Ativação Enzimática , Polarização de Fluorescência , Fígado/citologia , Masculino , Molsidomina/farmacologia , Doadores de Óxido Nítrico/farmacologia , Penicilamina/farmacologia , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidoresRESUMO
BACKGROUND: Tight junctions play a critical role in tubular function. In mammalian kidney, the transepithelial electrical resistance and the complexity of the tight junction increase from the proximal to the collecting tubule. The differential expression of three tight junction proteins, ZO-1, ZO-2, and occludin, along isolated rabbit renal tubules is examined in this article. METHODS: Microdissected rabbit renal tubules were processed for immunofluorescence detection of ZO-1, ZO-2, and occludin. The quantitation of these proteins was done by Western blot determinations in Percoll isolated tubules. RESULTS: ZO-1 stained cell boundaries independently of the identity of the tubule. However, the amount found in distal segments was significantly higher than that expressed in proximal regions. ZO-2 in the proximal region was found diffusely distributed in the cytoplasm, with faint staining at cell borders, while a clear signal at cell perimeters was detectable from the Henle's loop to collecting tubules. Nuclear staining of ZO-2 was found along the whole nephron. The presence of occludin at the proximal region was faint and discontinuous, while its expression in the more distant portions was conspicuous. The quantity of ZO-2 and occludin present at the distal region was significantly higher compared with the proximal segment. CONCLUSIONS: The distribution of ZO-1, ZO-2, and occludin follows the increase in junction complexity encountered in renal tubules. The amount of the three proteins found in proximal and distal segments is significantly higher in the latter.
Assuntos
Túbulos Renais/metabolismo , Proteínas de Membrana/metabolismo , Fosfoproteínas/metabolismo , Junções Íntimas/metabolismo , Animais , Western Blotting , Núcleo Celular/metabolismo , Imunofluorescência , Secções Congeladas , Técnicas In Vitro , Masculino , Ocludina , Coelhos , Distribuição Tecidual , Proteína da Zônula de Oclusão-1 , Proteína da Zônula de Oclusão-2RESUMO
Hepatic blood flow decreases under cholestasis and there is evidence that NO regulates liver microvascular perfusion. Thus, the aim of the present study was to evaluate NO synthesis in cholestasis. Cholestasis was induced by bile-duct ligation (BDL) in male Wistar rats. Bilirubins and enzyme activities were measured in serum. Lipid peroxidation, GSH, GSSG and glycogen were determined in liver. Histopathological analysis was performed. Serum NO2- + NO3- concentration was measured by the Gries reaction. iNOS immunoblot analysis was carried out using an iNOS polyclonal antibody. After 7 days of BDL lipid peroxidation increased while GSH/GSSG ratio decreased. Serum NO2- + NO3- and liver iNOS protein were reduced, accompanied by ischemia as revealed by the histopathological analysis. GSH upregulates NO synthesis by increasing iNOS mRNA levels and iNOS activity, thus the reduction of GSH/GSSG ratio may be responsible for the downregulation of iNOS protein and NO synthesis, which in turn may explain the observed ischemia and the decreased hepatic blood perfusion in cholestasis reported by others.
Assuntos
Colestase/metabolismo , Regulação para Baixo/fisiologia , Isquemia/metabolismo , Fígado/irrigação sanguínea , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico/biossíntese , Doença Aguda , Animais , Bilirrubina/sangue , Colestase/enzimologia , Eletroforese em Gel de Poliacrilamida , Glutationa/metabolismo , Immunoblotting , Isquemia/enzimologia , Fígado/metabolismo , Masculino , Óxido Nítrico Sintase/sangue , Óxido Nítrico Sintase Tipo II , Ratos , Ratos Wistar , Fluxo Sanguíneo RegionalRESUMO
The aim of this work was to evaluate the role of lipid peroxidation and glutathione on liver damage induced by 7-day biliary obstruction in the rat. Male Wistar rats were bile-duct-ligated and divided in groups of 10 animals. Groups received vitamin E (400 IU/rat, p.o., daily) or trolox (50 mg/kg, p.o., daily) or both. Lipid peroxidation increased significantly in the livers of bile-duct-ligated rats. Vitamin E and trolox prevented lipid peroxidation. GSH was oxidized in the BDL group and the GSH/GSSG ratio decreased as a consequence. However, total glutathione content increased in liver and blood indicating a possible induction in de novo synthesis of GSH. Antioxidants preserved the normal GSH/GSSG ratio. Despite the observation that antioxidants verted lipid peroxidation and oxidation of GSH, liver injury (as assessed by serum enzyme activities, bilirubin concentration, liver glycogen content and histology) was not affected by the treatments. These results suggest that drugs that inhibit lipid peroxidation and oxidation of glutathione have no effect on conventional biochemical markers of liver injury and on liver histology of bile-duct-ligated rats for 7 days. It seems more likely that the detergent action of bile salts is responsible for solubilization of plasma membranes and cell death, which in turn may lead to oxidative stress, GSH oxidation and lipid peroxidation.
Assuntos
Antioxidantes/farmacologia , Colestase/fisiopatologia , Glutationa/fisiologia , Peroxidação de Lipídeos , Animais , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Ratos , Ratos WistarRESUMO
The aim of this paper was to determine if NO modulation would influence liver damage induced by 3 day-biliary obstruction. L-Arginine (500 mg kg-1, p.o. twice a day) or L-NAME (100 mg kg-1, p.o. twice a day) or both were administered to male Wistar rats subjected to bile duct ligation (BDL). In the liver, BDL doubled lipid peroxidation and depleted glycogen (P < 0.05), L-arginine completely prevented the former and partially the latter. Alkaline phosphatase, alanine aminotransferase and gamma-glutamyl transpeptidase serum enzyme activities increased (P < 0.05) by BDL, again L-arginine treatment partially, but significantly, prevented the elevation in these three markers of liver damage. Although L-NAME treatment failed to induce a change in any marker of liver injury studied herein, it abolished the beneficial effects of L-arginine, suggesting that these effects are probably mediated by NO synthesis stimulation.
Assuntos
Arginina/farmacologia , Fígado/efeitos dos fármacos , Fígado/patologia , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Arginina/antagonistas & inibidores , Colestase/tratamento farmacológico , Colestase/patologia , Inibidores Enzimáticos/farmacologia , Glicogênio/metabolismo , Peróxidos Lipídicos/metabolismo , Fígado/enzimologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Ratos , Ratos Wistar , gama-Glutamiltransferase/sangueRESUMO
Interferons have been utilized widely in chronic liver diseases for their antiviral properties. In addition, there is evidence for their antifibrogenic actions. In this work we studied effects of various doses of interferon-alpha 2b on experimental liver fibrosis and cholestasis induced in the rat by biliary obstruction. Collagen was measured as hepatic hydroxyproline content. Cholestasis was determined by serum alkaline phosphatase and gamma-glutamyltranspeptidase activities and by bilirubin content. Glycogen was measured in the liver. Interestingly, the best effects (antifibrotic and anticholestatic) were observed in the group receiving the lowest dose of interferon. These results suggest that interferon-alpha 2b may be used at low doses, thereby decreasing side effects and costs.
Assuntos
Colestase Intra-Hepática/tratamento farmacológico , Interferon-alfa/uso terapêutico , Cirrose Hepática Experimental/tratamento farmacológico , Animais , Bilirrubina/sangue , Colestase Intra-Hepática/metabolismo , Colágeno/análise , Relação Dose-Resposta a Droga , Interferon alfa-2 , Fígado/metabolismo , Cirrose Hepática Experimental/metabolismo , Glicogênio Hepático/análise , Masculino , Ratos , Ratos Wistar , Proteínas RecombinantesRESUMO
Colchiceine and ursodeoxycholic acid (UDCA) are drugs currently in use as therapy for different types of liver damage. We evaluated their ability to reverse the damage induced by carbon tetrachloride (CCl4) in rats. Six groups were analysed: (1) CCl4 (0.4 g kg(-1), i.p., three times a week) for 13 weeks; (2) CCl4 for 8 weeks followed by colchiceine (60 microg kg(-1)) + CCl4 for 5 weeks; (3) CCl4 for 8 weeks and thereafter UDCA (25 mg kg(-1)) + CCl4 for 5 weeks. Groups 4, 5 and 6 were appropriate controls of colchiceine, UDCA and vehicles respectively. Na+,K+- and Ca2+-ATPase activities and the cholesterol-phospholipid (CH/PL) ratio from erythrocyte and hepatocyte membranes were quantified. Membrane enzymatic activities and CH/PL ratios were affected more in group 1 than groups 2 and 3. We concluded that colchiceine and UDCA were effective drugs in this model of liver damage.
Assuntos
Tetracloreto de Carbono/toxicidade , Colchicina/análogos & derivados , Membrana Eritrocítica/efeitos dos fármacos , Cirrose Hepática Experimental/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/patologia , Ácido Ursodesoxicólico/farmacologia , Animais , ATPases Transportadoras de Cálcio/sangue , ATPases Transportadoras de Cálcio/química , Colesterol/sangue , Colesterol/química , Colchicina/farmacologia , Colchicina/uso terapêutico , Membrana Eritrocítica/química , Membrana Eritrocítica/enzimologia , Cirrose Hepática Experimental/sangue , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/patologia , Masculino , Fosfolipídeos/sangue , Fosfolipídeos/química , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/sangue , ATPase Trocadora de Sódio-Potássio/química , Ácido Ursodesoxicólico/uso terapêuticoRESUMO
Interferons have been used to treat chronic hepatitis owing to their antiviral properties. However, now interferons are recognized to inhibit collagen production. Because fibrosis has been associated with liver damage and dysfunction, the effects of interferon-alpha 2b on biliary obstruction-induced cirrhosis were investigated. Obstructive jaundice was induced in male Wistar rats (ca. 200 g) by double ligation and division of the common bile duct. Control rats were sham operated. Interferon-alpha 2b (IFN-alpha; 1000 000 IU per rat) was administered subcutaneously daily after surgery. The animals were sacrificed after 4 weeks of bile duct ligation (BDL) or sham operation. Bilirubins and serum enzyme activities of alkaline phosphatase and gamma-glutamyl transpeptidase (determined as markers of liver damage) increased several-fold after BDL. Erythrocyte and hepatocyte plasma membrane Na+/K+- and Ca2+-ATPase activities decreased significantly in the BDL group. Administration of IFN-alpha to BDL rats resulted in a partial normalization of serum markers of liver damage. The normal activity of both ATPases on erythrocyte and hepatocyte plasma membranes was completely preserved by IFN-alpha. It is concluded that interferons possess interesting hepatoprotective effects not related to their antiviral properties but probably associated with their antifibrogenic effect.
Assuntos
Ductos Biliares/fisiologia , ATPases Transportadoras de Cálcio/efeitos dos fármacos , Membrana Eritrocítica/enzimologia , Interferon-alfa/farmacologia , Fígado/enzimologia , Fígado/patologia , ATPase Trocadora de Sódio-Potássio/efeitos dos fármacos , Animais , ATPases Transportadoras de Cálcio/sangue , Membrana Celular/efeitos dos fármacos , Membrana Celular/enzimologia , Membrana Eritrocítica/efeitos dos fármacos , Ligadura/efeitos adversos , Fígado/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/sangueRESUMO
There is poor evidence about the participation of lipoperoxidative processes in liver damage induced by biliary obstruction, thus the aim of this work was to study the role of lipid peroxidation in this model of liver injury. Biliary obstruction was induced in male Wistar rats by ligation of the common bile duct; control animals were sham operated. Rats were sacrificed at different times after surgery. Liver sections were used for glycogen and lipoperoxidation quantification. Markers of liver damage were determined in serum. All serum markers of liver damage increased after 1 day of biliary obstruction. Liver glycogen content decreased 1 day after surgery. On the other hand, lipoperoxidation increased later than markers of liver damage, suggesting that it is a consequence rather than the cause of liver injury. Moreover, administration of colchiceine (a good free-radical scavenger) or vitamin E prevented lipoperoxidation but not liver damage, confirming that lipoperoxidation does not play an important role in liver damage induced by biliary obstruction. This model of liver injury seems to be useful for testing hepatoprotective drugs that do not act as free-radical scavengers.
Assuntos
Colestase/metabolismo , Peroxidação de Lipídeos/fisiologia , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Ductos Biliares/cirurgia , Bilirrubina/sangue , Colestase/patologia , Colchicina/farmacologia , Sequestradores de Radicais Livres/farmacologia , Masculino , Ratos , Ratos Wistar , Vitamina E/farmacologia , gama-Glutamiltransferase/sangueRESUMO
In human and experimental CCl4-liver damage, S-adenosyl-l-methionine-synthetase and/or the intrahepatic content of S-adenosyl-l-methionine, are diminished and in human cirrhosis phospholipid methyltransferase is markedly reduced. Therefore the aim of this study was to investigate the effect of S-adenosyl-l-methionine administration on liver damage induced by 15-day bile duct ligation. Liver damage was analyzed by histological, ultrastructural and biochemical techniques. Biliary obstruction produced an increase in collagen content, dilation of the bile canaliculi and disorganization of mitochondria. These effects were not observed in the bile-duct-ligated group receiving S-adenosyl-l-methionine. Biochemical results showed that bile duct ligation increased serum bilirubins, and alkaline phosphatase and gamma-glutamyl transpeptidase activities. These effects were prevented significantly by S-adenosyl-l-methionine. On the other hand, glycogen content in the liver was depleted while lipid peroxidation was increased by biliary obstruction, S-adenosyl-l-methionine administration prevented these effects. In the bile-duct-ligated group, hepatocyte and erythrocyte plasma membrane Na+/K+ and Ca(2+)-ATPase were lower than in the control group (p < 0.05). Administration of S-adenosyl-l-methionine preserved ATPase activities. The exogenous S-adenosyl-l-methionine supply is probably responsible for restoring transmethylation lost in liver diseases.
Assuntos
Colestase/patologia , Colestase/prevenção & controle , Fígado/patologia , S-Adenosilmetionina/uso terapêutico , Análise de Variância , Animais , Ductos Biliares/fisiologia , ATPases Transportadoras de Cálcio/metabolismo , Membrana Celular/metabolismo , Membrana Celular/patologia , Membrana Celular/ultraestrutura , Colestase/metabolismo , Membrana Eritrocítica/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/ultraestrutura , Glicogênio Hepático/metabolismo , Masculino , Malondialdeído/metabolismo , Ratos , Ratos Wistar , Valores de Referência , S-Adenosilmetionina/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
The effect of colchicine on liver damage induced by acetaminophen (APAP) intoxication was studied. Wistar male rats pretreated (72 h) with 3-methylcholanthrene (3-MC) (20 mg/kg i.p.) were divided into six groups: animals in group 1 were treated with acetaminophen (APAP) (500 mg/kg p.o.); group 2 consisted of animals that received colchicine (65 micrograms/kg/day p.o.) for 7 days before APAP intoxication; group 3 was treated like group 2, but the dose of colchicine was 300 micrograms/kg/day; animals in groups 4 and 5 received the same doses of colchicine as groups 2 and 3, respectively, but received the vehicle instead of APAP; and rats in group 6 (control) received the equivalent amount of the vehicles. Animals were sacrificed at different times after APAP administration. Reduced glutathione (GSH), lipid peroxidation and glycogen were measured in liver and, gamma-glutamyl transpeptidase (gamma-GTP), and glutamic pyruvic transaminase (GPT) activities were measured in serum. After APAP intoxication, GSH and glycogen decreased very fast (1 h) and remained low for 6 h. Lipid peroxidation increased three times over control 4 h after APAP treatment. Enzyme activities increased at 18 h after intoxication. Pretreatment with 65 micrograms/kg of colchicine failed to prevent liver damage induced by APAP. However, when a dose of 300 micrograms/kg of colchicine was given, levels of lipid peroxidation and serum gamma-GTP activity remained within the control values, while GPT activity and glycogen content were only partially attenuated. It was concluded that colchicine protects against APAP intoxication, probably through its antioxidant properties, possibly acting as a free radical scavenger.
Assuntos
Acetaminofen/intoxicação , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Colchicina/uso terapêutico , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Sequestradores de Radicais Livres , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Pré-Medicação , Ratos , Ratos WistarRESUMO
The efficacy of silymarin treatment in preventing biochemical and histological alterations in CCL4-induced liver cirrhosis in rats was studied. Four groups of rats were treated with: (1) CCL4; (2) mineral oil; (3) CCL4 + silymarin; and (4) silymarin. All animals were sacrificed 72 h after the end of treatments. The activities of alkaline phosphatase (alk. phosp.), gamma-glutamyl transpeptidase (GGTP), glutamic pyruvic transaminase (GPT) and glucose-6-phosphatase (G6Pase), and bilirubin content were determined in serum. Na+, K+-ATPase and Ca++-ATPase activities were measured in isolated plasma membranes. Lipoperoxidation, triglycerides (TG), and glycogen contents were also measured in liver homogenates. Liver cirrhosis was evidenced by significant increases in liver collagen, lipoperoxidation, serum activities of alk. phosp., GGTP, GPT, G6Pase, bilirubin content, and liver TG. Activities of ATPases determined in plasma membranes were significantly reduced, as was liver glycogen content. Silymarin cotreatment (50 mg/kg b.wt) completely prevented all the changes observed in CCL4-cirrhotic rats, except for liver collagen content which was reduced only 30% as compared to CCL4-cirrhotic rats. Silymarin protection can be attributed to the agent's antioxidant and membrane-stabilizing actions.