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Int. j. morphol ; 38(1): 48-55, Feb. 2020. graf
Article in English | LILACS | ID: biblio-1056396


This research was designed to investigate the potential protective effect of vitamin C supplementation against hepatocyte ultrastructural alterations induced by artemether (antimalarial drug) administration. Twenty-four adult male albino rats were used in this study and were divided into four groups (n=6). Group I served as a control and rats in group II administrated artemether (4 mg/kg B.W) orally for three consecutive days. Group III administered artemether plus a low dose of vitamin C (2.86 mg/kg/l water) while group IV received artemether plusa high dose of vitamin C (8.56 mg/kg). At the end of the experimental period (14 days), the harvested liver tissues were examined by transmission electron microscopy (TEM), and blood samples were assayed for biomarkers of liver injury and oxidative stress. Artemether significantly (p<0.05) augmented biomarkers of liver injury such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and oxidative stress such as superoxide dismutase (SOD), Glutathione Peroxidase (GPX), and caused degeneration and damage of the rough endoplasmic reticulum and disrupted mitochondria. The blood sinusoids were also damaged with distortion of their canaliculi. Administration of vitamin C showed improvement of liver biomarkers, and liver parenchyma, especially in a high dose of vitamin C.We concludes that vitamin C is a partial protective agent against artemether-induced liver injury.

Esta investigación fue diseñada para investigar el posible efecto protector de la vitamina C contra las alteraciones ultraestructurales de los hepatocitos, inducidas por la administración de arteméter (medicamento antipalúdico). En el estudio se utilizaron 24 ratas albinas macho adultas y se dividieron en cuatro grupos (n = 6). El grupo I fue designado como control y las ratas en el grupo II se adminstró Arteméter (4 mg / kg de peso corporal) por vía oral durante tres días consecutivos. En el grupo III se administró arteméter, además de una dosis baja de vitamina C (2,86 mg / kg / l de agua) mientras que el grupo IV recibió arteméter más una dosis alta de vitamina C (8,56 mg / kg). Al final del período experimental (14 días), los tejidos hepáticos recolectados se examinaron por microscopía electrónica de transmisión (MET), y las muestras de sangre se analizaron en busca de biomarcadores de daño hepático y estrés oxidativo. El arteméter aumentó significativamente (p <0,05) los biomarcadores de daño hepático como alanina aminotransferasa (ALT), aspartato aminotransferasa (AST) y estrés oxidativo como superóxido dismutasa (SOD), glutatión peroxidasa (GPX) y causó degeneración y daño de la retículo endoplásmico rugoso y mitocondrias alteradas. Los sinusoides sanguíneos también fueron dañados con la distorsión de sus canalículos. La administración de vitamina C mostró una mejoría de los biomarcadores hepáticos y el parénquima hepático, especialmente en una dosis alta de vitamina C. Concluimos que la vitamina C es un agente protector parcial contra la lesión hepática inducida por arteméter.

Animals , Rats , Ascorbic Acid/administration & dosage , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Artemether/toxicity , Ascorbic Acid/pharmacology , Superoxide Dismutase/analysis , Biomarkers , Rats, Sprague-Dawley , Oxidative Stress/drug effects , Hepatocytes/drug effects , Hepatocytes/ultrastructure , Microscopy, Electron, Transmission , Disease Models, Animal , Hepatoprotector Drugs , Chemical and Drug Induced Liver Injury/pathology , Glutathione Peroxidase/analysis
Rev. Assoc. Med. Bras. (1992) ; 66(1): 12-17, Jan. 2020. tab, graf
Article in English | LILACS | ID: biblio-1091907


SUMMARY Drug-induced liver injury (DILI) to flucloxacillin is rare and is classified as idiosyncratic, as it is dependent on individual susceptibility, unpredictable, and dose-independent. The authors present the case of a 74 - year - old man with a history of monoclonal gammopathy under investigation and alcoholic habits of 24 g/day, with asthenia, anorexia, nausea, abdominal discomfort, and fever with three days of evolution. He was treated with two courses of antibiotic therapy with flucloxacillin to erysipelas previously (3 months and 2 weeks before admission). Lab tests showed serum AST levels of 349 U/L, ALT 646 U/L, alkaline phosphatase 302 U/L, GGT 652 U/L, total bilirubin 3.3 mg/dL and direct bilirubin 2.72 mg/dL. Infectious, autoimmune, and metabolic causes were ruled out. Magnetic resonance cholangiopancreatography showed normal results. Liver biopsy showed mild multifocal (predominantly microvesicular) steatosis; marked changes in the centrilobular areas (sinusoidal dilatation, marked congestion, hemorrhage, and multifocal hepatocyte collapse); expansion of the portal areas with the formation of bridges; proliferated bile ducts and inflammatory infiltrate of variable density, predominantly mononuclear type. The HLA-B*5701 screening test was positive. Hepatic biochemical tests remain abnormal with a significative increase in total bilirubin, which reached levels of 24.1 mg/dL, with the development of jaundice, pruritus, and choluria. DILI was assumed, and the patient was treated with ursodeoxycholic acid. There was favorable evolution, without evidence of blood coagulation dysfunction or encephalopathy. The analytic normalization was, however, slow, with evolution to chronicity. The authors present this case to remind the possibility of moderate/severe drug-induced liver injury to flucloxacillin, an antibiotic commonly used in clinical practice and association with the HLA-B * 5701 allele reported in the literature.

RESUMO A hepatotoxicidade à flucloxacilina é rara e classifica-se como idiossincrática, uma vez que é dependente da suscetibilidade individual, não expectável e independente da dose. Apresentamos o caso de um homem, 74 anos, antecedentes de gamapatia monoclonal e hábitos alcoólicos de 24 g/dia, com quadro de astenia, anorexia, náuseas, desconforto abdominal e febrícula com três dias de evolução. Referência a dois ciclos de antibioterapia com flucloxacilina por erisipela (três meses e duas semanas antes da admissão). Analiticamente com AST 349 U/L, ALT 646 U/L, FA 302 U/L, GGT 652 U/L, bilirrubina total 3,3 mg/dL, bilirrubina direta 2,72 mg/dL. Excluídas etiologias infecciosa, autoimune, metabólica, bem como patologia das vias biliares por colangio-RM. Biópsia hepática mostrou esteatose multifocal ligeira (predominantemente microvesicular); alterações acentuadas nas áreas centrolobulares (dilatação sinusoidal, congestão acentuada, hemorragia e colapso multifocal de hepatócitos); expansão das áreas portais com constituição de pontes; ductos biliares proliferados e infiltrado inflamatório de densidade variável, predominantemente de tipo mononucleado. Tipagem de HLA-B*5701 positiva. Agravamento analítico atingindo bilirrubina total 24,1 mg/dL, com desenvolvimento de icterícia, prurido e colúria. Admitida a hepatotoxicidade, iniciou terapêutica com ácido ursodesoxicólico. Verificou-se evolução favorável, sem evidência de coagulopatia ou encefalopatia. A normalização analítica foi, no entanto, lenta, com evolução para cronicidade. Os autores apresentam este caso para alertar para a possibilidade de hepatotoxicidade moderada a grave à flucloxacilina, antibiótico de uso comum na prática clínica e associação com o alelo HLA-B*5701 relatada na literatura.

Humans , Aged , HLA-B Antigens/drug effects , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/pathology , Floxacillin/adverse effects , Immunoelectrophoresis/methods , Risk Factors , Chemical and Drug Induced Liver Injury/enzymology , Liver/drug effects , Liver/pathology
Rev. méd. Chile ; 146(10): 1215-1219, dic. 2018. graf
Article in Spanish | LILACS | ID: biblio-978759


Abstrac: Before the advent of highly active antiretroviral therapy (HAART), patients infected with human immunodeficiency virus (HIV) were considered as having an absolute contraindication for liver transplantation (LT). Considering the increased life expectancy in HIV positive patients under HAART and the improvements in the management of graft recipients, these patients are now suitable for carrying out transplants in selected cases. We report a 26 years old HIV positive male who developed acute liver failure possibly caused by drug induced liver injury who underwent a successful liver transplantation.

Humans , Male , Adult , Acquired Immunodeficiency Syndrome/drug therapy , Liver Transplantation/methods , Antiretroviral Therapy, Highly Active/adverse effects , Chemical and Drug Induced Liver Injury/surgery , Treatment Outcome , Chemical and Drug Induced Liver Injury/pathology , Immunocompetence
Int. j. morphol ; 36(2): 661-669, jun. 2018. graf
Article in English | LILACS | ID: biblio-954169


Thioacetamide (TAA) is one of the common fungicidal agents that induce liver injury varying from inflammation, necrosis, and fibrosis to cirrhosis. Many recent studies reported the beneficial effect of probiotics and silymarin on hepatotoxicity regardless the causative agents. Therefore, the present study aimed to evaluate the ameliorative role of probiotics and/or silymarin on TAA induced hepatotoxicity in rats via histological, and immunohistochemical methods. Twenty five male albino rats were used for this experiment and were divided into five groups (n=5 rats/group); group I acts as negative control, group II was orally administrated distilled water for six weeks, then injected with TAA (200 mg/kg b.wt./ 5 ml physiological saline/ I.P.) twice a week for another six weeks, group III was treated with probiotics at a dose of 135 mg/ kg b.wt. orally in drinking water daily for six weeks, then injected with TAA (dosage of group II), twice weekly for another six weeks, group IV was treated with silymarin at a dose of 200 mg/ kg b.wt orally 4 times per week for six weeks, then injected with TAA (dosage of group II), twice weekly for another six weeks and group V was treated with combination of both probiotics and silymarin, at the same dosage in groups III and IV respectively then injected with TAA (dosage of group II), twice weekly for another six weeks. Histologically, TAA induced hepatocytes degeneration, inflammatory cells infiltration, and pseudolobular parenchyma as well as, high apoptosis and low proliferation rates that were proved by immunohistochemical staining for caspase 3 and ki-67 respectively. Probiotics and/or silymarin improved the histological feature of hepatocytes, reduced apoptosis and stimulated proliferation. Based on these results, we concluded that the use of probiotics and silymarin combination ameliorates the hepatotoxic effect of TAA in rats more than the use of probiotics or silymarin alone.

La tioacetamida (TAA) es uno de los agentes fungicidas más comunes que inducen lesiones hepáticas que varían desde inflamación, necrosis y fibrosis hasta cirrosis. Muchos estudios recientes informaron el efecto beneficioso de los probióticos y la silimarina sobre la hepatotoxicidad independientemente de los agentes causantes. Por lo tanto, el presente estudio tuvo como objetivo evaluar el papel paliativo de los probióticos y / o silimarina en la hepatotoxicidad inducida por TAA en ratas a través de métodos histológicos e inmunohistoquímicos. Para este experimento se usaron veinticinco ratas albinas y se dividieron en cinco grupos (n = 5 ratas / grupo); el grupo I se usó como control negativo; en el grupo II se administró por vía oral agua destilada durante seis semanas y luego se inyectó TAA (200 mg / kg b.wt./ 5 ml solución salina fisiológica / IP) dos veces por semana durante otras seis semanas; el grupo III se trató con probióticos, dosis diaria de 135 mg / kg b.wt. por vía oral en agua potable, durante seis semanas y luego fue inyectado con TAA (dosis del grupo II), dos veces por semana durante otras seis semanas; el grupo IV se trató con silimarina, con una dosis de 200 mg / kg b.wt por vía oral 4 veces por semana durante seis semanas, luego se inyectó TAA (dosificación del grupo II), dos veces por semana durante otras seis semanas; y el grupo V, se trató con una combinación de ambos probióticos y silimarina con la misma dosis que en los grupos III y IV, respectivamente, luego fueron inyectados con TAA (dosificación del grupo II), dos veces por semana durante otras seis semanas. Histológicamente, la TAA indujo la degeneración de los hepatocitos, la infiltración de células inflamatorias y el parénquima pseudolobular, así como también una apoptosis alta y tasas de proliferación bajas que se probaron mediante tinción inmunohistoquímica para caspasa 3 y ki-67, respectivamente. Los probióticos y / o la silimarina mejoraron la característica histológica de los hepatocitos, redujeron la apoptosis y estimularon la proliferación. En base a estos resultados, concluimos que el uso de la combinación de probióticos y silimarina mejora el efecto hepatotóxico del TAA en ratas más que el uso de probióticos o silimarina individualmente.

Animals , Male , Rats , Silymarin/administration & dosage , Thioacetamide/toxicity , Probiotics/administration & dosage , Chemical and Drug Induced Liver Injury/drug therapy , Immunohistochemistry , Chemical and Drug Induced Liver Injury/pathology , Liver/drug effects
Acta cir. bras ; 32(8): 633-640, Aug. 2017. graf
Article in English | LILACS | ID: biblio-886223


Abstract Purpose: To evaluate the effect of hyperin in cisplatin-induced liver injury in mice. Methods: Mice were pretreated with hyperin at doses of 25 mg/kg and 50 mg/kg, respectively, for six days, and intraperitoneal injection of cisplatin (40 mg/kg) was administrated one hour after the final intragastrication of hyperin. Twenty-four hours later, blood and liver were collected for further research. Results: A single injection of cisplatin (40 mg/kg) for 24 h significantly increased serum alanine and aspartate aminotransferases (ALT/AST) and gamma glutamyl transferase (GGT) activities, whileas hyperin reversed cisplatin-induced such increases. Liver histopathological examination further demonstrated the protection of hyperin against cisplatin-induced liver injury. Further results showed hyperin reversed cisplatin-induced the increase in content of malondialdehyde (MDA) and the decrease in level of total antioxidant capacity (T-AOC) in liver. Moreover, hyperin increased the levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), glutathione-s transferase (GST) in cisplatin-induced liver. Conclusion: Hyperin inhibits cisplatin-induced hepatic oxidative stress, which contributes greatly to the amelioration of cisplatin-induced liver injury in mice.

Animals , Male , Quercetin/analogs & derivatives , Aspartate Aminotransferases/metabolism , Cisplatin/adverse effects , Chemical and Drug Induced Liver Injury/prevention & control , Antineoplastic Agents/adverse effects , Antioxidants/pharmacology , Quercetin/therapeutic use , Quercetin/pharmacology , Reference Values , Lipid Peroxidation , Catalase/analysis , Random Allocation , Reproducibility of Results , Cisplatin/antagonists & inhibitors , Oxidative Stress/drug effects , Alanine Transaminase/metabolism , Chemical and Drug Induced Liver Injury/pathology , Glutathione/analysis , Glutathione Peroxidase/analysis , Glutathione Transferase/analysis , Liver/drug effects , Liver/enzymology , Liver/pathology , Malondialdehyde/analysis , Mice, Inbred ICR , Antioxidants/therapeutic use
Acta cir. bras ; 31(11): 724-729, Nov. 2016. graf
Article in English | LILACS | ID: biblio-827660


ABSTRACT PURPOSE: To investigate the hepatotoxicity and nephrotoxicity of 3-Bromopyruvate (3BP) in mice. METHODS: Fifteen nude mice were grafted subcutaneously in the left flank with MDA-MB-231 cells, then all mice were divided into control group (PBS), 3BP group (8 mg/kg), positive group (DNR: 0.8 mg/kg) when tumor volume reached approximately 100 mm3. 28 days later, tumors, livers and kidneys were stored in 4 % formalin solution and stained with hematoxylin and eosin staining. The Kunming mice experiment included control group (PBS), 3BP group (4mg/kg; 8mg/kg; 16mg/kg), positive group (DNR: 0.8 mg/kg). 24 hours later, the blood were used for the determination of hepatic damage serum biomarkers. Livers were stored in 4 % formalin solution for the later detection. RESULTS: 3BP at the dose of 8mg/kg had a good effect on inhibiting tumor growth in nude mice and did not damage liver and kidney tissues. Kunming mice experiment showed 3BP at the dose of 16mg/kg did damage to liver tissues. CONCLUSION: 3-Bromopyruvate at the dose of suppressing tumor growth did not exhibit hepatotoxicity and nephrotoxicity in nude mice, and the effect on liver was confirmed in Kunming mice.

Animals , Female , Mice , Pyruvates/toxicity , Enzyme Inhibitors/toxicity , Chemical and Drug Induced Liver Injury/pathology , Acute Kidney Injury/pathology , Kidney/drug effects , Liver/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Acute Kidney Injury/chemically induced , Liver Neoplasms, Experimental/drug therapy , Mice, Inbred BALB C , Mice, Nude
Rev. bras. anestesiol ; 66(5): 465-469, Sept.-Oct. 2016. graf
Article in English | LILACS | ID: lil-794808


Abstract Background and objectives: Inhalation anesthetics are used in human, as well as veterinary medical practice. In the present study we investigated the effect of isoflurane and sevoflurane on rat hepatocytes. Methods: A total of 40 Wistar female rats were used in this study. Animals were divided in groups of 5 rats. Groups IM, SM served as control groups. Groups I1, I2, I3 were used to study isoflurane and S1, S2, S3 for sevoflurane study. They were anesthetized 3 times, for 2 h long, at 2 days interval with a concentration of: 1.5% isoflurane (I1, I2, I3) and 2% sevoflurane (S1, S2, S3). The oxygen supply throughout the anesthesia was 1 L O2/min. Groups IM, IS, I1, S1 were sacrificed immediately after the last anesthesia. Groups I2, S2 were sacrificed 6 h after the last anesthesia, and groups I3, S3, 24 h post-anesthesia. Liver samples were harvested to highlight caspase-3 in apoptotic hepatocytes. Results: Following isoflurane administration, there were less than 1% cells in apoptosis highlighted in rat livers from groups IM, I1 and I2. At 24 h post-anesthesia (group I3), a small number of apoptotic hepatocytes was highlighted (around 3.23% cells in apoptosis), with a strictly periacinar disposition, randomly distributed in a small number of hepatic lobules. After sevoflurane administration, less than 1% apoptotic hepatocytes were identified at all control moments throughout the study. Conclusions: The results suggest that the anesthetics do not present a considerable hepatotoxicity. The comparative assessment of the two anesthetics shows that sevoflurane is superior to isoflurane.

Resumo Justificativa e objetivos: Anestésicos inalatórios são usados em humanos e também na prática médica veterinária. No presente estudo investigamos o efeito de isoflurano e sevoflurano em hepatócitos de rato. Métodos: Foram usados neste estudo 40 ratos Wistar fêmeas. Os animais foram divididos em grupos de cinco. Os grupos IM e SM serviram como controle. Os grupos I1, I2 e I3 foram usados para o estudo de isoflurano e os grupos S1, S2 e S3 para o estudo de sevoflurano. Os ratos foram anestesiados três vezes, durante duas horas em intervalos de dois dias, com uma concentração de 1,5% de isoflurano (I1, I2, I3) e 2% de sevoflurano (S1, S2, S3). O fornecimento de oxigênio durante a anestesia foi de 1 L O2/min. Os grupos IM, IS, I1 e S1 foram sacrificados imediatamente após a última anestesia. Os grupos I2 e S2 foram sacrificados seis horas após a última anestesia e os grupos I3 e S3 foram sacrificados 24 horas após a anestesia. Amostras dos fígados foram colhidas para ressaltar a caspase-3 em hepatócitos apoptóticos. Resultados: Após a administração de isoflurano, havia menos de 1% das células em apoptose em destaque nos fígados dos ratos dos grupos IM, I1 e I2. Às 24 horas após a anestesia (grupo I3), um pequeno número de hepatócitos apoptóticos foi destacado (3,23% de células em apoptose), com uma disposição estritamente periacinar, distribuídos aleatoriamente em um pequeno número de lóbulos hepáticos. Após a administração do sevoflurano, menos de 1% de hepatócitos apoptóticos foi identificado em todos os momentos de controle ao longo do estudo. Conclusões: Os resultados sugerem que os anestésicos não apresentam uma hepatotoxicidade considerável. A avaliação comparativa dos dois anestésicos mostra que sevoflurano é superior ao isoflurano.

Animals , Female , Anesthetics, Inhalation/toxicity , Chemical and Drug Induced Liver Injury/pathology , Isoflurane/toxicity , Liver/pathology , Methyl Ethers/toxicity , Immunohistochemistry , Rats, Wistar , Apoptosis/drug effects , Hepatocytes/drug effects , Hepatocytes/pathology , Dose-Response Relationship, Drug , Sevoflurane , Liver/drug effects
Braz. j. med. biol. res ; 49(12): e5647, 2016. tab, graf
Article in English | LILACS | ID: biblio-828176


The current study aimed to investigate the effects of perinatal exposure to nonylphenol (NP) on delivery outcome of pregnant rats and subsequent inflammatory hepatic injury in newborn rats. The pregnant rats were divided into 2 groups: control group (corn oil) and NP exposure group. Thirty-four pregnant rats were administered NP or corn oil by gavage from the sixth day of pregnancy to 21 days postpartum, with blood samples collected at 12 and 21 days of pregnancy and 60 days after delivery. The NP concentration was measured by HPLC, with chemiluminescence used for detection of estrogen and progesterone levels. Maternal delivery parameters were also observed. Liver and blood of the newborn rats were collected and subjected to automatic biochemical detection of liver function and blood lipid analyzer (immunoturbidimetry), and ultrastructural observation of the hepatic microstructure, with the TNF-α and IL-1β hepatic tissue levels evaluated by immunohistochemistry. Compared with the control group, the pregnant and postpartum serum NP and estradiol levels of the mother rats in the NP group were significantly increased, together with lowered progesterone level, increased number of threatened abortion and dystocia, and fewer newborn rats and lower litter weight. Serum and hepatic NP levels of the newborn rats measured 60 days after birth were significantly higher than those of the control group, as well as lower testosterone levels and increased estradiol levels. When observed under electron microscope, the hepatocyte nuclei of the control group were large and round, with evenly distributed chromatin. The chromatin of hepatocytes in the NP group presented deep staining of the nuclei, significant lipid decrease in the cytoplasm, and the majority of cells bonded with lysate. The results of immunohistochemistry showed that there was almost no TNF-α or IL-1β expression in the hepatocytes of the control group, while the number of TNF-α-, PCNA-, and IL-1β-positive cells in the NP group was increased, with higher integral optical density than the control group. Compared to the control group, the serum levels of alanine aminotransferase, aspartate aminotransferase, triglyceride and low-density lipoprotein in the newborn rats of the NP group were significantly increased. There was no significant difference in the serum level of high-density lipoprotein or cholesterol between the groups. Perinatal exposure to NP can interfere with the in vivo estrogen and progesterone levels of pregnant rats, resulting in threatened abortion, dystocia and other adverse delivery outcomes. High liver and serum NP levels of the newborn rats led to alteration of liver tissue structure and function. The NP-induced hepatotoxicity is probably mediated by inflammatory cytokines TNF-α and IL-1α.

Animals , Female , Rats , Chemical and Drug Induced Liver Injury/etiology , Phenols/toxicity , Animals, Newborn , Chemical and Drug Induced Liver Injury/pathology , Disease Models, Animal , Interleukin-1/analysis , Prenatal Exposure Delayed Effects/chemically induced , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/analysis
Acta cir. bras ; 30(11): 778-784, Nov. 2015. tab, graf
Article in English | LILACS | ID: lil-767597


PURPOSE: To investigate the possible protective effect of rutin on methotrexate induced hepatotoxicity in rats. METHODS: Twenty-two rats were divided into three experimental groups; Control-saline, Mtx, Mtx+Rutin. Hepatic tissue was taken for histological assessment and biochemical assays. Oxidative stress parameters malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were investigated. Liver markers aspartate aminotransferase (AST), alanine aminotransferase (ALT) were analyzed in serum. RESULTS: Mtx+Rutin group showed lower histological injury compared to Mtx group, MDA and ALT levels were increased, while SOD and GSH-Px were decreased in Mtx group compared with Control-saline group. MDA and ALT levels were increased, while SOD and GSH-Px were decreased in Mtx group, compared with Mtx +Rutin group. Serum AST levels were similar among the groups. CONCLUSION: Rutin may be a potential adjuvant drug to reduce the hepatic side effects observed during Mtx therapy for various clinical conditions.

Animals , Female , Chemical and Drug Induced Liver Injury/drug therapy , Immunosuppressive Agents/toxicity , Methotrexate/toxicity , Rutin/therapeutic use , Alanine Transaminase/blood , Antioxidants/pharmacology , Antioxidants/therapeutic use , Aspartate Aminotransferases/blood , Chemical and Drug Induced Liver Injury/pathology , Chemical and Drug Induced Liver Injury/prevention & control , Glutathione Peroxidase/analysis , Liver/drug effects , Liver/pathology , Malondialdehyde/analysis , Oxidative Stress/drug effects , Rats, Wistar , Reproducibility of Results , Rutin/pharmacology , Superoxide Dismutase/analysis
Säo Paulo med. j ; 133(4): 371-376, July-Aug. 2015. tab, graf
Article in English | LILACS | ID: lil-763366


CONTEXT:Nimesulide is a selective inhibitor of the enzyme cyclooxygenase 2. Although considered to be a safe drug, cases of acute hepatitis and fulminant liver failure have been reported in Europe, the United States and South America, especially among elderly female patients. Until now, there had not been any reports in the literature relating to Brazilian subjects.CASE REPORT:An 81-year old female who had been using nimesulide therapy for six days presented hematemesis and epistaxis two days before hospitalization. Clinical examination showed an extensive coagulation disorder, diffuse hematomas, hypotension and tachypnea. Laboratory tests revealed abnormalities in coagulation tests; leukocytosis; reduced platelet, hemoglobin and red blood cell counts; and elevated direct bilirubin, serum aspartate transaminase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase and renal function biomarkers. Hepatitis B and C tests were not reactive. Carcinoembryonic antigen (CEA), CA-19-9 and CA-125 levels were increased by, respectively, 1,000, 10,000 and 13 fold, whereas the alpha-fetoprotein level was normal, thus indicating a malignant tumor in the bile duct that did not originate from the liver. Thirty-six hours after hospitalization, the patient's condition worsened, leading to death. The necropsy findings included acute hepatitis with hepatocellular collapse, as well as metastasis of a carcinoma, probably from the bile duct.CONCLUSION:Despite the carcinoma presented by the patient, nimesulide use may have contributed towards the fatal acute liver failure. Until this issue has been clarified, caution is required in prescribing nimesulide for liver disease patients.

CONTEXTO:A nimesulida é um inibidor seletivo da enzima ciclo-oxigenase 2. Apesar de ela ser considerada fármaco seguro, casos de hepatite aguda e falência hepática fulminante foram descritos na Europa, Estados Unidos e América do Sul, principalmente em idosos do sexo feminino. Até o momento não há relatos na literatura em indivíduos brasileiros.RELATO DE CASO:Mulher de 81 anos, em uso terapêutico de nimesulida por seis dias, apresentou hematêmese e epistaxe dois dias antes da hospitalização. O exame clínico mostrou importante distúrbio de coagulação, hematomas difusos, hipotensão e taquipneia. Os exames laboratoriais mostravam alteração das provas de coagulação, leucocitose, redução do número de plaquetas, hemoglobina e hemácias, aumento de bilirrubina direta, elevação dos valores de aspartato aminotransferase (AST), gama glutamil transpeptidase (GGT), fosfatase alcalina e marcadores de função renal. Exames para hepatite B e C apresentaram-se não reagentes. Elevados níveis dos marcadores antígeno carcinoembriônico (CEA), CA-19-9 e CA-125 foram encontrados (1.000, 10.000 e 13 vezes, respectivamente), enquanto a alfa-fetoproteína estava normal, indicando um tumor maligno no ducto biliar, não oriundo do fígado. Trinta e seis horas após a hospitalização, a paciente evoluiu a óbito. Os achados necroscópicos incluíram hepatite aguda com colapso hepatocelular, bem como metástase de carcinoma, provavelmente do ducto biliar.CONCLUSÃO:Apesar do carcinoma apresentado pela paciente, o uso de nimesulida pode ter contribuído para o dano hepático. Até que esta questão seja esclarecida, a prescrição de nimesulida deve ser cuidadosa para pacientes com doenças hepáticas.

Aged, 80 and over , Female , Humans , Adenocarcinoma/secondary , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Liver Failure, Acute/chemically induced , Liver Neoplasms/pathology , Sulfonamides/adverse effects , Chemical and Drug Induced Liver Injury/pathology , Fatal Outcome , Liver Failure, Acute/pathology
Acta cir. bras ; 30(4): 247-252, 04/2015. tab, graf
Article in English | LILACS | ID: lil-744281


PURPOSE: To determine the antioxidant and anti-inflammatory effects of alfa lipoic acid (ALA) on the liver injury induced by methotrexate (MTX) in rats. METHODS: Thirty two rats were randomly assigned into four equal groups; control, ALA, MTX and MTX with ALA groups. Liver injury was performed with a single dose of MTX (20 mg/kg) to groups 3 and 4. The ALA was administered intraperitonealy for five days in groups 2 and 4. The other rats received saline injection. At the sixth day the rats decapitated, blood and liver tissue samples were removed for TNF-α, IL-1β, malondialdehyde, glutathione, myeloperoxidase and sodium potassium-adenosine triphosphatase levels measurement and histological examination. RESULTS: MTX administration caused a significant decrease in tissue GSH, and tissue Na+, K+ ATPase activity and which was accompanied with significant increases in tissue MDA and MPO activity. Moreover the pro-inflammatory cytokines (TNF-α, IL- β) were significantly increased in the MTX group. On the other hand, ALA treatment reversed all these biochemical indices as well as histopathological alterations induced by MTX. CONCLUSION: Alfa lipoic acid ameliorates methotrexate induced oxidative damage of liver in rats with its anti-inflammatory and antioxidant effects. .

Animals , Female , Male , Antimetabolites, Antineoplastic/toxicity , Antioxidants/therapeutic use , Chemical and Drug Induced Liver Injury/prevention & control , Methotrexate/toxicity , Thioctic Acid/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Chemical and Drug Induced Liver Injury/pathology , Enzyme-Linked Immunosorbent Assay , Glutathione/analysis , Interleukin-1beta/blood , Liver/drug effects , Liver/pathology , Malondialdehyde/analysis , Necrosis/pathology , Peroxidase/analysis , Random Allocation , Rats, Wistar , Reproducibility of Results , Treatment Outcome , Tumor Necrosis Factor-alpha/blood
Biol. Res ; 48: 1-9, 2015. ilus, graf, tab
Article in English | LILACS | ID: biblio-950783


BACKGROUND: To evaluate the hepatoprotective potential and invitro cytotoxicity studies of whole plant methanol extract of Rumex vesicarius L. Methanol extract at a dose of 100 mg/kg bw and 200 mg/kg bw were assessed for its hepatoprotective potential against CCl4-induced hepatotoxicity by monitoring activity levels of SGOT (Serum glutamic oxaloacetic transaminase), SGPT (Serum glutamic pyruvic transaminase), ALP (Alkaline phosphatase), TP (Total protein), TB (Total bilirubin) and SOD (Superoxide dismutase), CAT (Catalase), MDA (Malondialdehyde). The cytotoxicity of the same extract on HepG2 cell lines were also assessed using MTT assay method at the concentration of 62.5, 125, 250, 500 µg/ml. RESULTS: Pretreatment of animals with whole plant methanol extracts of Rumex vesicarius L. significantly reduced the liver damage and the symptoms of liver injury by restoration of architecture of liver. The biochemical parameters in serum also improved in treated groups compared to the control and standard (silymarin) groups. Histopathological investigation further corroborated these biochemical observations. The cytotoxicity results indicated that the plant extract which were inhibitory to the proliferation of HepG2 cell line with IC50 value of 563.33 ± 0.8 Mg/ml were not cytotoxic and appears to be safe. CONCLUSIONS: Rumex vesicarius L. whole plant methanol extract exhibit hepatoprotective activity. However the cytotoxicity in HepG2 is inexplicable and warrants further study.

Humans , Animals , Male , Rats , Plant Extracts/pharmacology , Cytotoxins/pharmacology , Rumex/chemistry , Cell Proliferation/drug effects , Chemical and Drug Induced Liver Injury/drug therapy , Phytotherapy/methods , Aspartate Aminotransferases/metabolism , Silymarin/pharmacology , Superoxide Dismutase/metabolism , Tetrazolium Salts , Bilirubin/metabolism , Carbon Tetrachloride , Catalase/metabolism , Anticarcinogenic Agents/pharmacology , Rats, Wistar , Alanine Transaminase/metabolism , Methanol , Drinking/drug effects , Eating/drug effects , Alkaline Phosphatase/metabolism , Hep G2 Cells , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Formazans , Liver/drug effects , Liver/metabolism , Malondialdehyde/metabolism , Antioxidants/metabolism , Antioxidants/pharmacology
Article in Spanish | LILACS | ID: lil-795825


A preclinical pharmacological study was conducted to evaluate the hepatoprotective effect of Mentha piperita L. against paracetamol induced toxicity. Adult male NMRI mice who were administered orally soft plant extracts in doses of 200mg/kg and 400mg/kg, three consecutive days prior to the induction of hepatotoxicity were used. Clinical signs of toxicity, hepatic biochemical parameters and morphological analysis of the liver was evaluated. The biochemical parameters analyzed showed significant differences, but none of the two groups showed a similar untreated control group behavior. No macroscopic changes in the liver were confirmed. Microscopically, the study groups with Mentha piperita L. showed mild to moderate damage with significant differences from the untreated control group. The evaluation of hepatoprotective potential on the M. piperita L. extract at doses studied did not behave as hepatoprotective agent...

Se realizó un estudio farmacológico preclínico para evaluar el efecto hepatoprotector de Mentha piperita L. frente a la toxicidad inducida por el paracetamol. Se emplearon ratones adultos machos NMRI a los que se administró por vía oral extractos blandos de la planta a dosis de 200 mg/kg y 400 mg/kg, tres días consecutivos previos a la inducción de la hepatotoxicidad. Se evaluaron los signos clínicos de toxicidad, parámetros bioquímicos hepáticos y el análisis morfológico del hígado. Los parámetros bioquímicos analizados mostraron diferencias altamente significativas, pero ninguno de los dos grupos presentaron un comportamiento similar al grupo control no tratado. No se confirmaron alteraciones macroscópicas del hígado. A nivel Microscópico, los grupos en estudio con Mentha piperita L. presentaron daños de leves a moderados con diferencias significativas respecto al grupo control no tratado. Se puede afirmar que según la evaluación del potencial hepatoprotector del extracto de M. piperita L. a las dosis estudiadas no se comportó como agente hepatoprotector...

Male , Animals , Mice , Acetaminophen/toxicity , Chemical and Drug Induced Liver Injury/drug therapy , Plant Extracts/administration & dosage , Liver/pathology , Mentha piperita/chemistry , Administration, Oral , Analgesics, Non-Narcotic/toxicity , Chemical and Drug Induced Liver Injury/pathology
Indian J Exp Biol ; 2014 Mar; 52(3): 207-214
Article in English | IMSEAR | ID: sea-150350


The alcoholic extract of stem of E. pursaetha (PSE, 30, 100, 300 mg/kg body weight, po for 7 days) showed hepatoprotective activity against CCl4 (2 mL/kg body weight, ip)-induced hepatotoxicity. The extract exhibited a significant dose-dependent hepatoprotective effect comparable to standard drug silymarin, by preventing increase in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total protein, and total bilirubin, lactate dehydrogenase; by lowering hepatic levels of malonaldehyde, nitrate-nitrite, myeloperoxidase activity; enhancing activities of antioxidant enzymes, superoxide dismutase, catalase and increasing reduced glutathione levels in liver, which suggests the antioxidant property of PSE. Histopathological studies also supported the above biochemical parameters. The results suggested that alcoholic extract of E. pursaetha possesses significant hepatoprotective activity in CCl4-induced acute hepatotoxicity in rats and this is likely to be mediated through its antioxidant activities.

Animals , Antioxidants/metabolism , Carbon Tetrachloride/toxicity , Catalase/metabolism , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/pathology , Fabaceae/chemistry , Glutathione/metabolism , Lipid Peroxidation/drug effects , Liver/drug effects , Liver/pathology , Plant Extracts/administration & dosage , Plant Extracts/chemistry , Rats , Superoxide Dismutase/metabolism
Braz. j. med. biol. res ; 47(2): 128-134, 2/2014. graf
Article in English | LILACS | ID: lil-699777


The liver is one of the target organs damaged by septic shock, wherein the spread of endotoxins begins. This study aimed to investigate the effects of exogenous normal lymph (ENL) on lipopolysaccharide (LPS)-induced liver injury in rats. Male Wistar rats were randomly divided into sham, LPS, and LPS+ENL groups. LPS (15 mg/kg) was administered intravenously via the left jugular vein to the LPS and LPS+ENL groups. At 15 min after the LPS injection, saline or ENL without cell components (5 mL/kg) was administered to the LPS and LPS+ENL groups, respectively, at a rate of 0.5 mL/min. Hepatocellular injury indices and hepatic histomorphology, as well as levels of P-selectin, intercellular adhesion molecule 1 (ICAM-1), myeloperoxidase (MPO), and Na+-K+-ATPase, were assessed in hepatic tissues. Liver tissue damage occurred after LPS injection. All levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma as well as the wet/dry weight ratio of hepatic tissue in plasma increased. Similarly, P-selectin, ICAM-1, and MPO levels in hepatic tissues were elevated, whereas Na+-K+-ATPase activity in hepatocytes decreased. ENL treatment lessened hepatic tissue damage and decreased levels of AST, ALT, ICAM-1, and MPO. Meanwhile, the treatment increased the activity of Na+-K+-ATPase. These results indicated that ENL could alleviate LPS-induced liver injury, thereby suggesting an alternative therapeutic strategy for the treatment of liver injury accompanied by severe infection or sepsis.

Animals , Male , Chemical and Drug Induced Liver Injury/therapy , Lymph , Alanine Transaminase/blood , Aspartate Aminotransferases/blood , Disease Models, Animal , Chemical and Drug Induced Liver Injury/pathology , Intercellular Adhesion Molecule-1/metabolism , Lipopolysaccharides , Rats, Wistar , Specific Pathogen-Free Organisms
Biol. Res ; 47: 1-7, 2014. ilus, graf
Article in English | LILACS | ID: biblio-950745


BACKGROUND: The liver is an important organ for its ability to transform xenobiotics, making the liver tissue a prime target for toxic substances. The carotenoid bixin present in annatto is an antioxidant that can protect cells and tissues against the deleterious effects of free radicals. In this study, we evaluated the protective effect of bixin on liver damage induced by carbon tetrachloride (CCl4) in rats. RESULTS: The animals were divided into four groups with six rats in each group. CCl4 (0.125 mL kg-1 body wt.) was injected intraperitoneally, and bixin (5.0 mg kg-1 body wt.) was given by gavage 7 days before the CCl4 injection. Bixin prevented the liver damage caused by CCl4, as noted by the significant decrease in serum aminotransferases release. Bixin protected the liver against the oxidizing effects of CCl4 by preventing a decrease in glutathione reductase activity and the levels of reduced glutathione and NADPH. The peroxidation of membrane lipids and histopathological damage of the liver was significantly prevented by bixin treatment. CONCLUSION: Therefore, we can conclude that the protective effect of bixin against hepatotoxicity induced by CCl4 is related to the antioxidant activity of the compound.

Animals , Male , Rats , Carbon Tetrachloride/antagonists & inhibitors , Carotenoids/pharmacology , Reactive Oxygen Species/analysis , Oxidative Stress/drug effects , Chemical and Drug Induced Liver Injury/prevention & control , Antioxidants/pharmacology , Plant Extracts/chemistry , Lipid Peroxidation/drug effects , Carotenoids/chemistry , Rats, Wistar , Bixaceae/chemistry , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Glutathione/analysis , Glutathione Reductase/drug effects , Transaminases/blood , Liver/enzymology , Malondialdehyde/analysis , NADP/analysis
Acta cir. bras ; 28(7): 526-530, July 2013. tab
Article in English | LILACS | ID: lil-679085


PURPOSE: To investigate the effects of copaiba oil on the hepatic damage induced by paracetamol. METHODS: Thirty six rats were distributed into six study groups (N=6): control group, that didn't receive the acetaminophen; Acetaminophen Group, that only received the acetaminophen; Prophylactic Copaiba Group 1, that received copaiba oil two hours before the acetaminophen; Prophylactic Copaiba Group 7, that received copaiba oil seven days, once by day, before the acetaminophen; Therapy Copaiba Group, that received the copaiba oil two hours afther the acetaminophen; and N-Acetyl-Cysteine Group, , that received the N-Acetyl-Cysteine two hours afther the acetaminophen. Euthanasia was performed after 24 hours. The serum levels of AST, ALT, alkaline phosphatase, GT, total bilirubin, direct bilirubin and indirect bilirubin and histological analisis were analized. RESULTS: The prophylactic copaiba group 7, therapy copaiba group and N-Acetyl-Cysteine Group showed amounts of AST and ALT similar to the control group; and the prophylactic copaiba group 1 showed similar levels to the acetaminophen group. There was no significant difference between the groups regarding the amount of alkaline phosphatase and GT (p>0.05). The therapy copaiba group showed the highest levels of bilirubin and was statistically different from the other groups (p<0.01) and this increased the costs of direct bilirubin. Regarding histopathology, the oil of copaiba administered prophylactic or therapeutic form for 7 days could decrease the amount of necrosis and inflammatory infiltrate. CONCLUSION: Copaiba oil administered prophylactically for seven days, and therapeutic could reduce liver damage caused by paracetamol similarly N-Acetyl-Cysteine, however, when treated with copaiba therapeutically showed increases in bilirubin, costs increasing fraction indirect.

Animals , Male , Rats , Acetaminophen/adverse effects , Analgesics, Non-Narcotic/adverse effects , Chemical and Drug Induced Liver Injury/drug therapy , Fabaceae/chemistry , Plant Oils/therapeutic use , Bilirubin/blood , Chemical and Drug Induced Liver Injury/pathology , Random Allocation , Rats, Wistar , Reproducibility of Results , Time Factors , Treatment Outcome
Acta cir. bras ; 27(12): 897-904, dez. 2012. ilus, graf, tab
Article in English | LILACS | ID: lil-657975


PURPOSE: To evaluate hepatic morphological-histological abnormalities in newborns from female rats exposed to ethylenethiourea. METHODS: A randomized study was conducted on fifty-five newborn Wistar rats were studied: 34 in the experimental group, whose mothers had been exposed to 1% ethylenethiourea; and 21 in the control group, whose mothers had received 0.9% physiological solution. The solution was administered via gavage on the 11th day of gestation. Cesarean section was performed on the 20th day of gestation. The newborns' livers were examined and any morphological-histological abnormalities were registered. The presence of megakaryocytes was quantified in 50 microscope fields, as the total number of these cells per mm². RESULTS: The entire experimental group presented abnormalities of embryonic formation, with musculoskeletal anomalies, digestive system anomalies, hepatic congestion and friability, hydrops and delayed intrauterine growth. The histopathological analysis showed that morphological-histological hepatic destructuring had occurred in all entire experimental with removal of the hepatic trabeculae and severe hepatic megakaryocytosis. The mean megakaryocyte density ranged from 107.9 to 114.2 per mm², and it was eight times greater than in the control group, thus characterizing a situation of extramedullary hematopoiesis. CONCLUSION: The fetal exposure to ethylenethiourea caused hepatic damage characterized by severe extramedullary hematopoiesis.

OBJETIVO: Avaliar alterações hepáticas morfohistológicas em recém-nascidos de ratas prenhes expostas à etilenotioureia. MÉTODOS: Realizado ensaio randomizado em animais de experimentação, onde foram estudados 55 recém-nascidos de ratas Wistar, 34 do Grupo Experimento, expostas a etilenotioureia 1% e 21 do Grupo Controle, em que a rata prenhe recebeu solução fisiológica 0,9%, ambos por gavagem no 11º dia de gestação. Realizada no 20º dia de gestação cesariana, analisados os fígados dos recém-nascidos e registradas as alterações morfohistológicas. Realizou-se a quantificação dos megacariócitos em 50 campos microscópicos, avaliando a quantidade total destas células por mm². RESULTADOS: Todos os recém-nascidos do Grupo Experimento apresentaram alterações na formação embrionária, com anomalias musculoesqueléticas, anormalidades do sistema digestório, congestão e friabilidade hepática, hidropisia e crescimento intrauterino retardado. A análise histopatológica mostrou desestruturação hepática morfohistológica em todos os recém-nascidos expostos à etilenotioureia, com destrabeculação dos hepatócitos e intensa megacariocitose hepática, apresentando média da densidade de megacariócitos de 107,9 até 114,2 por mm² sendo cerca de oito vezes maior que no Grupo Controle, caracterizando hematopoese extramedular. CONCLUSÃO: A exposição fetal a etilenotioureia provocou danos hepáticos caracterizados pela intensa hematopoese extramedular.

Animals , Female , Pregnancy , Rats , Chemical and Drug Induced Liver Injury/pathology , Ethylenethiourea/toxicity , Pesticides/toxicity , Prenatal Exposure Delayed Effects/pathology , Animals, Newborn , Chemical and Drug Induced Liver Injury/etiology , Hematopoiesis, Extramedullary/drug effects , Models, Animal , Prenatal Exposure Delayed Effects/chemically induced , Random Allocation , Rats, Wistar
Yonsei Medical Journal ; : 172-180, 2012.
Article in English | WPRIM | ID: wpr-145835


PURPOSE: Toxicity caused by acetaminophen and its toxic mechanisms in the liver have been widely studied, including effects involving metabolism and oxidative stress. However, its adverse effects on heart have not been sufficiently investigated. This study evaluated the cardiac influence and molecular events occurring within the myocardium in rats treated with a dose of acetaminophen large enough to induce conventional liver damage. MATERIALS AND METHODS: Male rats were orally administered a single dose of acetaminophen at 1,000 mg/kg-body weight, and subsequently examined for conventional toxicological parameters and for gene expression alterations to both the heart and liver 24 hours after administration. RESULTS: Following treatment, serum biochemical parameters including aspartate aminotransferase and alanine aminotransferase were elevated. Histopathological alterations of necrosis were observed in the liver, but not in the heart. However, alterations in gene expression were observed in both the liver and heart 24 hours after dosing. Transcriptional profiling revealed that acetaminophen changed the expression of genes implicated in oxidative stress, inflammatory processes, and apoptosis in the heart as well as in the liver. The numbers of up-regulated and down-regulated genes in the heart were 271 and 81, respectively, based on a two-fold criterion. CONCLUSION: The induced expression of genes implicated in oxidative stress and inflammatory processes in the myocardium reflects molecular levels of injury caused by acetaminophen (APAP), which could not be identified by conventional histopathology.

Acetaminophen/toxicity , Administration, Oral , Analgesics, Non-Narcotic/toxicity , Animals , Chemical and Drug Induced Liver Injury/pathology , Gene Expression Profiling , Heart/physiology , Liver/pathology , Male , Myocardium/pathology , Rats , Transcriptome/drug effects