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Rev. cuba. hematol. inmunol. hemoter ; 37(3): e1505, 2021. tab
Article in Spanish | LILACS, CUMED | ID: biblio-1341404


Introducción: Con el protocolo LPM-TOA para el tratamiento de la leucemia promielocítica se obtienen excelentes resultados, se prolonga la sobrevida global y es posible la curación de los enfermos. En la de inducción a la remisión se utilizan dos drogas, una antraciclina y trióxido de arsénico, y en la consolidación los enfermos reciben de nuevo una dosis elevada de arsénico. Objetivo: Evaluar la toxicidad hepática tardía en pacientes con leucemia promielocítica tratados según el protocolo LPM-TOA. Métodos: Se realizó estudio longitudinal prospectivo que incluyó20 pacientes tratados con dicho protocolo, todos con más de dos años de haberlo suspendido. Se revisaron las historias clínicas para evaluar mediante los valores iniciales y evolutivos de las enzimas hepáticas, la función hepática inicial y evolutiva. Se determinó el índice de Ritis para predecir evolución a la cronicidad de existir daño hepático. Resultados: Hombres y mujeres se presentaron con la misma frecuencia y la media para la edad del sexo masculino fue 36,39 y para el femenino 39, con desviación estándar de ±14,02 y ±9,43, respectivamente. La variedad morfológica más frecuente fue la hipergranular, el promedio del índice de Ritis fue de solo 1,006 con desviación estándar de 0,745. Conclusiones: No hubo evidencias clínica ni enzimática de toxicidad hepática tardía en los pacientes estudiados(AU)

Introduction: With the LPM-TOA protocol for the treatment of acute promyelocytic leukemia, excellent results are obtained, overall survival is prolonged and the patients are cured, in the induction to remission two drugs are used, an anthracycline and arsenic trioxide, and in consolidation the patients again receive a high dose of arsenic. Objective: To assess late liver toxicity in patients with promyelocytic leukemia treated according to the PML-TOA protocol. Methods: A prospective longitudinal study was carried out that included 20 patients treated with this protocol, all with more than two years of having suspended treatment. The clinical histories were reviewed and by means of the initial and evolutionary values of liver enzymes, the initial and evolutionary liver function was evaluated and the Ritis index was determined to predict evolution to chronicity if there is liver damage. Results: Men and women presented with the same frequency and the mean age for males was 36.39 and for females it was 39, with a standard deviation of ± 14.02 and ± 9.43 respectively. The most frequent morphological variety was hypergranular, the average Ritis index was only 1.006 with a standard deviation of 0.745. Conclusions: There was no clinical or enzymatic evidence of late liver toxicity in the patients studied(AU)

Humans , Leukemia, Promyelocytic, Acute/drug therapy , Chemical and Drug Induced Liver Injury/prevention & control , Arsenic Trioxide/toxicity , Survival Analysis , Prospective Studies , Longitudinal Studies
Article in Chinese | WPRIM | ID: wpr-879150


To explore the effect of light intensity in cultivating environment on the hepetoprotective activity of Sedum sarmentosum, S. sarmentosum were planted under five water treatments for 60 days, namely 100% full sunlight(G1), 77% full sunlight(G2), 60% full sunlight(G3), 38% full sunlight(G4), and 16% full sunlight(G5) and CCl_4 drug-induced liver injury model in vitro was used. Cell viability, cell cycle, and cell apoptosis were individually detected by MTT, PI single staining, and Annexin-V FITC/PI double staining assays. Additionally, ALT, AST and antioxidant index in supernatant were determined by colorimetry. And the relationship among the protective effects, chemical composition and antioxidant activity were also analyzed. The results showed that S. sarmentosum aqueous extract could significantly improve the HepG2 cell viability. Among the five S. sarmentosum groups, the cell viability of G1(100% full sunlight) treatment was the highest, and the cell apoptosis was the least. Meanwhile, the level of ALT, AST, and MDA in G1 was the lowest, but it achieved the highest level of SOD and GSH. Moderate light shading(60% full light) also improved the effect of protecting liver and reducing the enzyme. It was found that cell viability was positively correlated with ferricion reducing capacity. ALT activity was positively correlated with isorhamnetin content. Taken together, different light intensity had great influence on hepatoprotective effect of S. sarmentosum, which may be related to its antioxidant capacity. From the perspective of hepetoprotective activity, S. sarmentosum should be planted under full light.

Antioxidants , Chemical and Drug Induced Liver Injury , Hep G2 Cells , Humans , Liver , Plant Extracts/pharmacology , Sedum , Water
Article in Chinese | WPRIM | ID: wpr-879086


Methotrexate(MTX) is a commonly used antimetabolite, which can be used in the treatment of a variety of diseases. However, hepatotoxicity in the use of MTX severely limits its clinical use. Therefore, how to prevent and treat hepatotoxicity of MTX has become an urgent clinical problem. This paper summarizes and analyzes relevant literatures on the prevention and treatment of hepa-totoxicity caused by MTX with traditional Chinese medicines and natural medicines in recent years. MTX-induced hepatotoxicity mechanisms include folate pathway, oxidative stress damage and adenosine pathway, of which oxidative stress theory is the main research direction. A total of 14 kinds of traditional Chinese medicine and natural medicine extracts including white peony root, and 21 kinds of natural monomer compounds, including berberine, play an anti-MTX-induced hepatotoxic effect by resisting oxidative stress, inhibiting inflammation and regulating signal pathways. According to current studies on the prevention and treatment of hepatotoxicity induced by MTX with traditional Chinese medicines and natural medicines, there are insufficiencies, such as partial and superficial mechanism studies, inadequate combination of experimental research and clinical practice, non-standard experimental design and lack of application of advanced technologies and methods. This paper systematically reviewed the effects and mechanisms of traditional Chinese medicines and natural medicines against hepatotoxicity induced by MTX and defined current studies and deficiencies, in the expectation of proposing new study strategies and directions and providing scientific basis for rational clinical use of MTX and development of new drugs against MTX hepatotoxicity.

Chemical and Drug Induced Liver Injury/prevention & control , Drug-Related Side Effects and Adverse Reactions , Humans , Liver/metabolism , Medicine, Chinese Traditional , Methotrexate/toxicity , Oxidative Stress
Article in Chinese | WPRIM | ID: wpr-878975


Liver is the main place of drug metabolism. Mitochondria of hepatocytes are important targets of drug-induced liver injury. Mitochondrial autophagy could maintain the healthy operation of mitochondria in cells and the stable proliferation of cells. Therefore, the use of mitochondrial autophagy to remove damaged mitochondria is an important strategy of anti-drug-induced liver injury. Active ingredients that could enhance mitochondrial autophagy are contained in many traditional Chinese medicines, which could regulate the mitochondrial autophagy to alleviate relevant diseases. However, there are only a few reports on how to accurately and efficiently identify and evaluate such components targeting mitochondria from traditional Chinese medicine. Liquid chromatography-mass spectro-metry(LC-MS) combined with serum pharmacology in vivo can be used to accurately and efficiently find active ingredients of traditional Chinese medicine acting on mitochondrial targets. This paper reviewed the research ideas and methods of traditional Chinese medicine ingredients for increasing the hepatotoxicity of mitochondrial autophagy, in order to provide new ideas and methods for the study of active ingredients of traditional Chinese medicine targeting mitochondria.

Chemical and Drug Induced Liver Injury , Drug-Related Side Effects and Adverse Reactions , Drugs, Chinese Herbal/toxicity , Humans , Medicine, Chinese Traditional , Mitochondria
Article in Chinese | WPRIM | ID: wpr-888115


As a common disease worldwide, alcoholic liver injury is caused by long-term or excessive intake of alcohol and triggers cell death due to alcohol metabolism and reactive oxygen species(ROS)-mediated cytotoxicity. Wangshi Baochi(WSBC) Pills have been widely adopted in clinical practice for evacuating stasis, resolving turbidity, clearing heat, tranquilizing mind, invigorating sto-mach, promoting digestion, purging fire and removing toxin. This study aimed to investigate the efficacy of WSBC Pills in dispelling the effect of alcohol and protecting against acute alcoholic liver/stomach injury in mice, and preliminarily investigate its possible mole-cular mechanism. The results found that the preventive treatment with WSBC Pills contributed to elevating the activity of alcohol dehydrogenase(ADH) and its expression in liver and shortening the time required for sobering up of mice with acute alcoholic liver injury. The staining of liver pathological sections as well as the detection of serum aspartate aminotransferase(AST) and alanine aminotransferase(ALT) and liver ROS levels revealed that WSBC Pills protected the liver by reducing serum AST and ALT. It suppressed oxidative stress-induced liver injury by lowering liver ROS and elevating superoxide dismutase(SOD), and the liver-protecting effect was superior to that of silibinin. Western blot assay confirmed that WSBC Pills inhibited the oxidative stress by up-regulating SOD1 and NAD(P)H: quinone oxidoreductase 1(NQO-1). In addition, WSBC Pills lowered the ROS level to protect against the acute alcoholic stomach injury in mice. The findings have suggested that WSBC Pills alleviated the acute alcoholic liver/stomach injury in mice by increasing ADH and resisting oxidative stress.

Animals , Chemical and Drug Induced Liver Injury , Ethanol , Liver/metabolism , Liver Diseases, Alcoholic , Mice , Oxidative Stress , Stomach
Article in English | WPRIM | ID: wpr-922758


Tripterygium wilfordii multiglycoside (GTW) is a commonly used compound for the treatment of rheumatoid arthritis (RA) and immune diseases in clinical practice. However, it can induce liver injury and the mechanism of hepatotoxicity is still not clear. This study was designed to investigate GTW-induced hepatotoxicity in zebrafish larvae and explore the mechanism involved. The 72 hpf (hours post fertilization) zebrafish larvae were administered with different concentrations of GTW for three days and their mortality, malformation rate, morphological changes in the liver, transaminase levels, and histopathological changes in the liver of zebrafish larvae were detected. The reverse transcription-polymerase chain reaction (RT-PCR) was used to examine the levels of microRNA-122 (miR-122) and genes related to inflammation, apoptosis, cell proliferation and liver function. The results showed that GTW increased the mortality of zebrafish larvae, while significant malformations and liver damage occurred. The main manifestations were elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), significant liver atrophy, vacuoles in liver tissue, sparse cytoplasm, and unclear hepatocyte contours. RT-PCR results showed that the expression of miR-122 significantly decreased by GTW; the mRNA levels of inflammation-related genes il1β, il6, tnfα, il10, cox2 and ptges significantly increased; the mRNA level of tgfβ significantly decreased; the mRNA levels of apoptosis-related genes, caspase-8 and caspase-9, significantly increased; the mRNA level of bcl2 significantly decreased; the mRNA levels of cell proliferation-related genes, top2α and uhrf1, significantly reduced; the mRNA levels of liver function-related genes, alr and cyp3c1, significantly increased; and the mRNA level of cyp3a65 significantly decreased. In zebrafish, GTW can cause increased inflammation, enhanced apoptosis, decreased cell proliferation, and abnormal expression of liver function-related genes, leading to abnormal liver structure and function and resulting in hepatotoxicity.

Animals , Apoptosis , Chemical and Drug Induced Liver Injury/genetics , Inflammation/genetics , Trans-Activators , Tripterygium , Zebrafish/genetics , Zebrafish Proteins
Article in English | WPRIM | ID: wpr-922110


OBJECTIVE@#To analyze clinical feature and information of medication to explore the risk signals of preparations containing Psoraleae Fructus (BGZP) related with hepatobiliary adverse drug reactions (ADR), in order to reinforce pharmacovigilance.@*METHODS@#A retrospective study was conducted based on hepatobiliary ADR related with BGZP from the China Adverse Drug Reaction Monitoring System in years from January 2012 to December 2016. Serious and general ADRs were analyzed and assessed.@*RESULTS@#There were 355 cases of hepatobiliary ADR related to BGZP. Both the amount of cases and the proportion of serious ADR showed an increasing growth by years (P<0.05). It was found that 10.43% of 355 cases may be involved with irrational drug use, including overdose, repeated medication, and combination of multiple drugs. There were 190 cases which used BGZP (non-combination), and they were mainly for common in diseases caused by abnormal immune activation (accounting for 40.53% of the total cases). Especially at the age group with the most cases with age of 41-50 years, the cases associated with immunological diseases of female were obviously more than that of male (P<0.05). The latency of hepatobiliary ADR related to BGZP ranged from 1 to 386 days, and the median latency was 27.5 days, along with the range of cumulative dose (0.45-520.02 g) as well as the daily dose (0.09-2.64 g/d) after the conversion.@*CONCLUSIONS@#Cases of hepatobiliary ADR related to BGZP showed significant individual differences, and there was no correlation between drug usage duration and dosage and the occurrence of hepatobiliary ADR. It may be similar with idiosyncratic drug-induced liver injury, and recommended that BGZP should be used with more caution under monitoring liver function, especially in female patients with immunological diseases.

Adult , Adverse Drug Reaction Reporting Systems , Chemical and Drug Induced Liver Injury/etiology , Drug-Related Side Effects and Adverse Reactions , Female , Humans , Male , Middle Aged , Pharmacovigilance , Retrospective Studies
Article in Chinese | WPRIM | ID: wpr-922037


OBJECTIVE@#To investigate the association between single nucleotide polymorphism of NUDT15 gene (SNP rs116855232) and hepatotoxicity in children with acute lymphocytic leukemia (ALL).@*METHODS@#A total of 135 children with ALL in Shandong Province were recruited in this study, and patients were divided into two groups based on the presence of liver injury. Genotypes of each patient were detected using PCR and Sanger sequencing. Clinical data and the average dose of 6-mercaptopurine (6-MP) were collected and analyzed by SPSS 19.0 software.@*RESULTS@#Respectively, 99 patients were found with CC genotype, 32 patients with CT genotype and 4 patients with TT genotype. Compared with ALL patients without hepatotoxicity, there was a difference in genotypes between the two groups in the initial stage of chemotherapy for leukemia (Chi@*CONCLUSION@#The polymorphism of rs116855232 in NUDT15 gene was associated with hepatotoxicity induced by 6-mercaptopurine in children with ALL, and ALL patients with TT genotype should take a lower dose of 6-MP to avoided hepatotoxicity.

Antimetabolites, Antineoplastic/therapeutic use , Chemical and Drug Induced Liver Injury/genetics , Child , Genotype , Humans , Mercaptopurine/adverse effects , Polymorphism, Single Nucleotide , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Pyrophosphatases/genetics
Acta Physiologica Sinica ; (6): 901-908, 2021.
Article in Chinese | WPRIM | ID: wpr-921294


The aim of the present study was to investigate the effects of dexmedetomidine (DEX) on acute liver injury induced by lipopolysaccharide (LPS)/D-galactosamine (D-Gal) and the underlying mechanism. Male BALB/c mice were intraperitoneally injected with LPS/D-Gal to induce acute liver injury model, and pretreated with DEX or in combination with the autophagy inhibitor, 3-methyladenine (3-MA) 30 min before injection. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, as well as myeloperoxidase (MPO) activity in liver tissue were determined with the corresponding kits. Serum tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) levels were determined by ELISA. The protein expression levels of LC3-II and P62 in liver tissue were determined by Western blot. Liver histopathological changes were detected by HE staining. The results showed that, compared with control group, LPS/D-Gal enhanced ALT and AST activity, increased TNF-α and IL-6 levels, as well as MPO activity, up-regulated LC3-II and P62 protein expression levels, and significantly induced pathological damage in liver tissue. DEX reversed the above changes in the LPS/D-Gal group, whereas these protective effects of DEX were blocked by 3-MA. The above results suggest that DEX alleviates LPS/D-Gal-induced acute liver injury, which may be associated with the up-regulation of LC3-II protein expression and the activation of autophagy.

Alanine Transaminase , Animals , Chemical and Drug Induced Liver Injury/drug therapy , Dexmedetomidine/pharmacology , Galactosamine/toxicity , Interleukin-6/blood , Lipopolysaccharides/toxicity , Liver , Male , Mice , Mice, Inbred BALB C , Microtubule-Associated Proteins/metabolism , Tumor Necrosis Factor-alpha/blood , Up-Regulation
Pesqui. vet. bras ; 41: e06893, 2021. tab, graf
Article in English | LILACS, VETINDEX | ID: biblio-1340360


This study describes an outbreak of acute necrotic hepatopathy associated with spontaneous poisoning by Lantana camara L. in dairy cattle. A herd of 15 cows and heifers was introduced into a native pasture with limited food supply, and, sixteen days later, eight animals had spontaneous nasal hemorrhage, fever, lethargy, jaundice, and dry, dark stools with mucus and blood. The clinical course varied from two to five days. In the pasture where the cattle were kept, abundant adult specimens of L. camara L. with evident signs of consumption were observed. In total, seven cattle died and necropsy was performed in three of them. All animals had moderate jaundice, hemorrhage in the subcutaneous tissue and on the surface of different organs. The liver was slightly enlarged, with orange discoloration and enhanced lobular pattern. Histologically, multifocal areas of coagulative necrosis of hepatocytes in the centrilobular area, occasionally extending to the midzonal area, were observed, as well as marked hepatocellular degeneration and prominent cholestasis. The current study suggests that L. camara L. poisoning should be considered a differential diagnosis of acute and necrotic hepatotoxicity in cattle, despite the absence of photosensitization.(AU)

Esse estudo descreve um surto de hepatopatia necrótica aguda associada a intoxicação espontânea por Lantana camara L. em bovinos leiteiros. Um lote de 15 vacas e novilhas foram introduzidas em um piquete com campo nativo, com escassa oferta de alimento. Após dezesseis dias, oito animais manifestaram epistaxe, febre, apatia, icterícia, fezes ressecadas e escuras com muco e sangue. A evolução do quadro clínico variou de dois a cinco dias. No piquete em que os bovinos estavam alojados havia grande quantidade de L. camara L. com sinais evidentes de consumo. No total, sete bovinos morreram, e destes, o exame post mortem foi realizado em três. Os bovinos exibiam moderada icterícia, hemorragias no tecido subcutâneo e na superfície de diferentes órgãos. O fígado estava discretamente aumentado, com coloração alaranjada e padrão lobular evidente. As lesões histológicas consistiam em acentuada necrose de coagulação de hepatócitos em região centrolobular, por vezes se estendendo a região mediozonal, além de acentuada degeneração dos hepatócitos e evidente Colestase. O presente trabalho alerta para que intoxicação por L. camara L. seja levada em consideração nos diagnósticos diferenciais de hepatotoxicidade necrótica aguda em bovinos, mesmo sem indícios de fotossensibilização.(AU)

Animals , Female , Cattle , Cattle , Lantana/toxicity , Eating , Chemical and Drug Induced Liver Injury/veterinary , Liver Diseases , Plants, Toxic
Frontiers of Medicine ; (4): 594-607, 2021.
Article in English | WPRIM | ID: wpr-888746


Psoraleae Fructus (PF) is a well-known traditional herbal medicine in China, and it is widely used for osteoporosis, vitiligo, and other diseases in clinical settings. However, liver injury caused by PF and its preparations has been frequently reported in recent years. Our previous studies have demonstrated that PF could cause idiosyncratic drug-induced liver injury (IDILI), but the mechanism underlying its hepatotoxicity remains unclear. This paper reports that bavachin isolated from PF enhances the specific stimuli-induced activation of the NLRP3 inflammasome and leads to hepatotoxicity. Bavachin boosts the secretion of IL-1β and caspase-1 caused by ATP or nigericin but not those induced by poly(I:C), monosodium urate crystal, or intracellular lipopolysaccharide. Bavachin does not affect AIM2 or NLRC4 inflammasome activation. Mechanistically, bavachin specifically increases the production of nigericin-induced mitochondrial reactive oxygen species among the most important upstream events in the activation of the NLRP3 inflammasome. Bavachin increases the levels of aspartate transaminase and alanine aminotransferase in serum and hepatocyte injury accompanied by the secretion of IL-1β via a mouse model of lipopolysaccharide-mediated susceptibility to IDILI. These results suggest that bavachin specifically enhances the ATP- or nigericin-induced activation of the NLRP3 inflammasome. Bavachin also potentially contributes to PF-induced idiosyncratic hepatotoxicity. Moreover, bavachin and PF should be evaded among patients with diseases linked to the ATP- or nigericin-mediated activation of the NLRP3 inflammasome, which may be a dangerous factor for liver injury.

Adenosine Triphosphate , Animals , Chemical and Drug Induced Liver Injury/etiology , Flavonoids , Humans , Inflammasomes , Mice , NLR Family, Pyrin Domain-Containing 3 Protein , Nigericin
Rev. Ciênc. Méd. Biol. (Impr.) ; 19(3): 449-456, dez 5, 2020. fig
Article in Portuguese | LILACS | ID: biblio-1357950


Introdução: o fármaco ranelato de estrôncio (RE) é muito utilizado na terapêutica profilática e no controle da osteoporose. Age sistemicamente diminuindo a reabsorção e aumentando a formação óssea, apresentando eventos adversos pouco esclarecidos na literatura, à exemplo a síndrome DRESS com envolvimento hepático. Objetivo: avaliar a morfologia hepática em ratos norvegicus albinus após administração do RE. Metodologia: estudo experimental com 10 ratos, divididos aleatoriamente em dois grupos, Grupo Controle (GC), sem administração do RE, e Grupo Ranelato de Estrôncio (GRE), ambos acompanhados durante 15 dias, e, em seguida, sacrificados e o fígado de cada animal colocado para fixação no solução de formaldeído a 4% durante 48 horas. Após essa etapa, foram realizados os procedimentos necessários à análise pela microscopia óptica, com lâminas coradas pela hematoxilina e eosina, e picrosirius red.Resultados: nos GC e GRE foram encontradas alterações similares, como reação ductular, dilatação sinusoidal e fibrose perissinusoidal, com intensidades distintas entre os grupos, sendo a reação ductular mais proeminente no GC, e a dilatação sinusoidal e fibrose perissinusoidal mais pronunciada no GRE. Além disso, no GC foram evidenciados achados inflamatórios, como presença de infiltrado inflamatório misto e hiperplasia de células de Kupffer, não visualizados no GRE, implicando numa possível ação anti-inflamatória do RE. Conclusão: pode-se concluir que foram visualizadas diferenças nos achados morfológicos do parênquima hepático dos ratos tratados com o RE em comparação aos não tratados, ainda que esses achados não sejam suficientes para inferir a incidência de um processo patológico característico, como cirrose ou hepatite.

Introduction: the drug strontium ranelate (SR) is widely used in prophylactic therapy and in the control of osteoporosis. It acts by reducing reabsorption and increasing bone formation systemically, presenting unclear adverse events in the literature, such as the DRESS syndrome with hepatic involvement. Objective: to evaluate hepatic morphology in norvegicus albinus rats after SR administration. Methodology: experimental group with 10 rats, divided into two groups, randomly distributed, five from the Control Group (CG), without SR administration, and the other five from the Strontium Ranelate Group (SRG), both followed for 15 days, and then sacrificed and the liver of each animal placed for fixation in 4% formalin for 48 hours. After this step, the procedures necessary for the analysis by optical microscopy were performed, with blades stained by hematoxylin e eosin, and picrosirius red. Results: in CG and SRG, similar alterations were observed, such as ductular reaction, sinusoidal dilatation and perissinusoidal fibrosis, with distinct intensities between the groups, being the ductular reaction more prominent in the CG, and sinusoidal dilation and a perissinusoidal fibrosis more pronounced in the SRG. In addition, in the CG were evidenced inflammatory findings such as the presence of mixed inflammatory infiltrate and Kupffer cell hyperplasia, not visualized in the SRG, implying a possible anti-inflammatory action of SR. Conclusion: it can be concluded that differences were observed in the morphological findings of the hepatic parenchyma of rats treated with SR compared to untreated rats, although these findings are not sufficient to infer the incidence of a characteristic pathological process, such as cirrhosis or hepatitis.

Animals , Male , Rats , Rats , Pharmaceutical Preparations , Chemical and Drug Induced Liver Injury , Rats, Inbred Strains
Int. j. morphol ; 38(5): 1444-1454, oct. 2020. tab, graf
Article in English | LILACS | ID: biblio-1134461


SUMMARY: Over dose or long-term clinical use of therapeutic doses of acetaminophen (APAP) causes hepatotoxicity. Various strategies attempted to ameliorate APAP-hepatotoxicity have been found to be unsuitable for clinical practice. This study was aimed to illustrate the histopathological changes induced by therapeutic dose of APAP and investigate the hepatoprotective role of oral co-administration of selenium/ Tribulus terrestris (TT) extract concurrently against hepatotoxicity induced by APAP in rats. Fifty-four healthy male albino Wistar rats were randomized into nine groups (G1-G9) of six rats each, and administered with APAP and TT orally for 30 days as follows: Control (2ml normal saline), APAP (470 mg/kg), APAP (470 mg/kg) + selenium (2 mg/kg), APAP (470 mg/kg) + TT (98 mg/kg), APAP (470 mg/kg) + selenium (2mg/kg) + TT (98 mg/kg), APAP (470 mg/kg) + silymarin (200 mg/kg), selenium (2 mg/ kg), TT (98 mg/kg) and silymarin (200 mg/kg) groups. The results demonstrated that exposure of rats to therapeutic dose of APAP for 30 days caused significant histopathological changes parallel to elevated blood chemistry parameters. Co-administration of selenium/TT extract showed significantly reduced histopathological lesions and, restored or decreased levels of the examined blood chemistry parameters. Liver histology in selenium/TT extract showed normal hepatic architecture with mild changes and silymarin treated rats showed no histopathological changes. Histochemically PAS staining, showed that APAP-induced hepatotoxicity was characterized by hepatocytes glycogen depletion. Selenium/TT co-supplementation plays a potential role in preventing APAP-induced glycogen depletion by increasing detoxification and scavenging the reactive metabolites. Selenium/TT extract oral co-administration possesses a significant hepatoprotective property and mitigates APAP-induced hepatotoxicity by enhancing its antioxidant role and improving tissue integrity. Selenium/TT supplementation could represent an effective treatment against APAP-induced hepatotoxicity. Further studies are needed to elucidate the exact mechanism underlying the protective role of TT extract.

RESUMEN: La dosis excesiva o el uso clínico a largo plazo de dosis terapéuticas de acetaminofeno (APAP) causa hepatotoxicidad. Se ha descubierto que varias estrategias que intentaron mejorar la hepatotoxicidad por APAP no son adecuadas para la práctica clínica. Este estudio tuvo como objetivo ilustrar los cambios histopatológicos inducidos por la dosis terapéutica de APAP e investigar el papel hepatoprotector de la administración conjunta de extracto de selenio / Tribulus terrestris (TT) simultá- neamente contra la hepatotoxicidad inducida por APAP en ratas. Cincuenta y cuatro ratas Wistar albino machos sanas se aleatorizaron en nueve grupos (G1 - G9) de seis ratas cada una, y se administraron con APAP y TT por vía oral durante 30 días de la siguiente manera: Control (2 ml de solución salina normal), APAP (470 mg / kg), APAP (470 mg / kg) + selenio (2 mg / kg), APAP (470 mg / kg) + TT (98 mg / kg), APAP (470 mg / kg) + selenio (2 mg / kg) + TT (98 mg / kg), APAP (470 mg / kg) + silimarina (200 mg / kg), selenio (2 mg / kg), TT (98 mg / kg) y silimarina (200 mg / kg). Los resultados demostraron que la exposición de las ratas a la dosis terapéutica de APAP durante 30 días causó cambios histopatológicos significativos paralelos a parámetros elevados de química sanguínea. La administración conjunta de extracto de selenio / TT mostró lesiones histopatológicas significativamente reducidas y niveles restaurados o disminuidos de los parámetros de química sanguínea. La histología hepática en el extracto de selenio / TT mostró una arquitectura hepática normal con cambios leves y las ratas tratadas con silimarina no mostraron cambios histopatológicos. La tinción histoquímica de PAS mostró que la hepatotoxicidad inducida por APAP se caracterizó por la pérdida de glucógeno de los hepatocitos. La suplementación con selenio / TT juega un papel potencial en la prevención de la pérdida de glucógeno inducido por APAP al aumentar la desintoxicación y eliminar los metabolitos reactivos. La administración conjunta de extracto de selenio / TT posee una propiedad hepatoprotectora significativa y mitiga la hepatotoxicidad inducida por APAP al mejorar su papel antioxidante y la integridad del tejido. La suplementación con selenio / TT podría representar un tratamiento efectivo contra la hepatotoxicidad inducida por APAP. Se necesitan más estudios para dilucidar el mecanismo exacto que subyace a la función protectora del extracto TT.

Animals , Male , Rats , Selenium/administration & dosage , Plant Extracts/administration & dosage , Tribulus/chemistry , Chemical and Drug Induced Liver Injury/drug therapy , Acetaminophen/toxicity , Administration, Oral , Rats, Wistar , Glycogen , Liver/drug effects
Int. j. morphol ; 38(3): 558-564, June 2020. tab, graf
Article in English | LILACS | ID: biblio-1098287


Chronic hepatotoxicity is a debilitating and frequently life-threatening disease resulting in progressive liver failure. The toxic chemical, thioacetamide (TAA) is used to evaluate hepatoprotective agents, and the polyphenolic compound, resveratrol was proposed as a novel treatment for diseases with hyperactivation of the mammalian target of rapamycin (mTOR) cell signaling pathway. This analysis sought to investigate the potential protective effect of resveratrol against liver injury induced by TAA via the inhibition of hepatic mTOR. Model group rats received several injections of TAA (200 mg/kg; twice a week for 8 weeks) before being sacrificed at week 10 and the protective group was pretreated with resveratrol (20 mg/kg) daily for two weeks prior to TAA injections and continued receiving both agents until the end of the experiment. Harvested liver tissues were examined using light microscopy and liver homogenates were assayed for biomarkers of inflammation and assessed the levels of mTOR protein in all animal groups. In addition, blood samples were assayed for biomarkers of liver injury enzyme. TAA substantially damaged the hepatic tissue of the model group such as infiltration of inflammatory cells, vacuolated cytoplasm, dark pyknotic nuclei, and dilated congested blood vessel that were effectively protected by resveratrol. Resveratrol also significantly (p<0.05) inhibited TAA-induced mTOR, high sensitivity c-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in harvested liver homogenates and blood samples. Thus, we conclude that resveratrol effectively protects against TAA-induced hepatotoxicity in rats, possibly due to the inhibition of mTOR and inflammation.

La hepatotoxicidad crónica es una enfermedad debilitante y potencialmente mortal que produce insuficiencia hepática progresiva. La toxicidad del químico de la tioacetamida (TAA) se utiliza para evaluar los agentes hepatoprotectores y el compuesto polifenólico, resveratrol, se propuso como un nuevo tratamiento para enfermedades con hiperactivación de la vía de señalización celular mTOR (mammalian Target of Rapamycin). Aquí buscamos investigar el posible efecto protector del resveratrol contra la lesión hepática inducida por TAA a través de la inhibición de la vía de señalización mTOR en hepatocitos. Las ratas del grupo modelo recibieron varias inyecciones de TAA (200 mg / kg; dos veces por semana durante 8 semanas) antes de ser sacrificadas en la semana 10 y el grupo protector se trató previamente con resveratrol (20 mg / kg) diariamente durante dos semanas antes de las inyecciones de TAA y continuó recibiendo ambos agentes hasta el final del experimento. Se examinaron los tejidos hepáticos recolectados usando microscopía óptica y se analizaron los homogeneizados hepáticos para detectar biomarcadores de inflamación y se evaluaron los niveles de proteína mTOR en todos los grupos de animales. Además, se analizaron muestras de sangre para detectar biomarcadores de la enzima de lesión hepática. TAA dañó sustancialmente el tejido hepático del grupo modelo, con infiltración de células inflamatorias, citoplasma vacuolado, núcleos picnóticos oscuros y vasos sanguíneos congestionados dilatados que estaban efectivamente protegidos por el resveratrol. El resveratrol también inhibió significativamente (p <0.05) mTOR, proteína C-reactiva (hs-CRP), factor de necrosis tumoral alfa (TNF-α), interleucina-6 (IL-6), alanina aminotransferasa (ALT ) y aspartato aminotransferasa (AST) en las muestras de sangre y de hígados recolectados. En conclusión, el resveratrol protege eficazmente contra la hepatotoxicidad inducida por TAA en ratas, posiblemente debido a la inhibición de mTOR y de la inflamación.

Animals , Male , Mice , Thioacetamide/toxicity , Chemical and Drug Induced Liver Injury/drug therapy , TOR Serine-Threonine Kinases/antagonists & inhibitors , Resveratrol/administration & dosage , Aspartate Aminotransferases/analysis , C-Reactive Protein/analysis , Tumor Necrosis Factor-alpha/analysis , Alanine Transaminase/analysis , Disease Models, Animal
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
Int. j. morphol ; 38(1): 83-90, Feb. 2020. tab, graf
Article in English | LILACS | ID: biblio-1056402


We sought to determine whether the combined polyphenolic compounds, resveratrol and quercetin can substantially protect against modulation of hepatic biomarkers of apoptosis and survival, p53-Bax axis and B-cell lymphoma 2 (Bcl-2) in an animal model of acetaminophen-induced acute liver injury via the association of oxidative stress and interleukin-11 (IL-11). The model group of rats received a single dose of acetaminophen (2 g/kg), whereas the protective group of rats was pre-treated for 7 days with combined doses of resveratrol (30 mg/kg) and quercetin (50 mg/kg) before being given a single dose of acetaminophen. All rats were then sacrificed 24 hours post acetaminophen ingestion. Acetaminophen overdose induced acute liver injury as demonstrated by profound liver parenchymal damage and increased levels of the liver injury enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Acetaminophen significantly (p<0.05) modulated malondialdehyde (MDA), p53, apoptosis regulator Bax, Bcl-2, IL-11, interleukin-6 (IL-6), ALT, AST, superoxide dismutase (SOD), and glutathione peroxidase (GPx), which were significantly protected by resveratrol plus quercetin. We further demonstrated a significant (p<0.01) correlation between IL-11 scoring and the levels of p53, Bax, Bcl-2, and MDA. Thus, resveratrol plus quercetin effectively protect against acetaminophen-induced apoptosis, which is associated with the inhibition of oxidative stress and IL-11.

En el estudio se intentó determinar si los compuestos polifenólicos combinados, el resveratrol y la quercetina pueden proteger sustancialmente contra la modulación de los biomarcadores hepáticos de apoptosis y supervivencia, el eje p53-Bax y el linfoma de células B 2 (Bcl-2) en un modelo animal de lesión hepática aguda inducida por acetaminofén, a través de la asociación del estrés oxidativo y la interleucina-11 (IL-11). El grupo modelo de ratas recibió una dosis única de acetaminofén (2 g / kg), mientras que el grupo protector de ratas fue tratado durante 7 días con dosis combinadas de resveratrol (30 mg / kg) y quercetina (50 mg / kg) antes de recibir una dosis única de acetaminofén. Todas los animales fueron sacrificados 24 horas después de la ingestión de acetaminofén. La sobredosis de acetaminofén indujo una lesión hepática aguda, como se observó en el daño profundo del parénquima hepático y el aumento de los niveles de las enzimas en la lesión hepática, alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST). Acetaminofén moduló significativamente (p <0.05) malondialdehído (MDA), p53, regulador de apoptosis Bax, Bcl2, IL-11, interleucina-6 (IL-6), ALT, AST, superóxido dismutasa (SOD) y glutatión peroxidasa ( GPx), los que se encontraron significativamente protegidos por el resveratrol y quercetina. Además se determinó una correlación significativa (p <0.01) entre la puntuación de IL-11 y los niveles de p53, Bax, Bcl-2 y MDA. En conclusión, el resveratrol más la quercetina protegen de manera efectiva contra la apoptosis inducida por acetaminofén, asociada con la inhibición del estrés oxidativo y la IL-11.

Animals , Rats , Quercetin/administration & dosage , Apoptosis/drug effects , Chemical and Drug Induced Liver Injury, Chronic/pathology , Resveratrol/administration & dosage , Acetaminophen/toxicity , Antioxidants/administration & dosage , Quercetin/pharmacology , Aspartate Aminotransferases/analysis , Biomarkers , Interleukin-1 , Oxidative Stress , Alanine Transaminase/analysis , Disease Models, Animal , Chemical and Drug Induced Liver Injury/enzymology , Resveratrol/pharmacology , Antioxidants/pharmacology
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
Biosci. j. (Online) ; 36(1): 245-255, jan./feb. 2020. tab, ilus
Article in English | LILACS | ID: biblio-1049246


Paracetamol (PCM) overdose can cause hepatotoxicity with oxidative stress; the present study was carried out to establish the possible protective effect of olive leaves extract (OLE) on toxicity induced by paracetamol in adult male rats. Twenty four adult male rats were divided into four equal groups; control, olive leaves extract group, paracetamol group and olive leaves extract plus paracetamol group. Some biochemical parameters and liver histopathology were evaluated. PCM treatment significantly increased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, gamma-glutamyltransferase (GGT), lactate dehydrogenase (LDH), urea, creatinine and alpha-fetoprotein. Paracetamol was found to significantly increase malonaldehyde (MDA) and decrease glutathione reductase (GR) activity in tissue and significantly decrease total antioxidant capacity (TAC) and superoxide dismutase (SOD) in serum. Administration of OLE caused a significant decrease serum AST, ALT enzyme, total bilirubin, GGT, LDH, creatinine, urea, alpha-fetoprotein. Also, amelioration of oxidant ­ antioxidant status with olive leaves extract was observed in addition to a significant decrease in MDA and a significant increase in TAC in liver tissue with a significant increase in glutathione reductase (GR) and SOD in serum compared to paracetamol treated group The chemical pathological changes were in step with histopathological observation suggesting marked hepatoprotective result of olive leaves extract. It could be concluded that olive leaves extract (OLE) treatment may be effective in decreasing hepatic injury and oxidative stress induced by paracetamol overdose in male albino rats

A sobredosagem de paracetamol (PCM) pode causar hepatotoxicidade com estresse oxidativo; o presente estudo foi realizado para estabelecer o possível efeito protetor do extrato de folhas de oliveira (OLE) na toxicidade induzida pelo paracetamol em ratos machos adultos. Vinte e quatro ratos machos adultos foram divididos em quatro grupos iguais: controle, grupo extrato de folhas de oliveira, grupo paracetamol e extrato de folhas de oliveira mais grupo paracetamol. Alguns parâmetros bioquímicos e histopatologia hepática foram avaliados. O tratamento com PCM aumentou significativamente aspartato aminotransferase sérica (AST), alanina aminotransferase (ALT), bilirrubina total, gama-glutamiltransferase (GGT), lactato desidrogenase (LDH), uréia, creatinina e alfa-fetoproteína. Verificou-se que o paracetamol aumenta significativamente o malonaldeído (MDA) e diminui a atividade da glutationa redutase (GR) no tecido e diminui significativamente a capacidade antioxidante total (TAC) e a superóxido dismutase (SOD) no soro. A administração de OLE causou uma diminuição significativa de AST, enzima ALT, bilirrubina total, GGT, LDH, creatinina, uréia, alfa-fetoproteína. Também foi observada melhora do status oxidante - antioxidante com extrato de folhas de oliveira, além de uma diminuição significativa no MDA e um aumento significativo no TAC no tecido hepático, com um aumento significativo na glutationa redutase (GR) e SOD no soro em comparação ao grupo tratado com paracetamol. As alterações patológicas químicas acompanharam a observação histopatológica, sugerindo resultado hepatoprotetor acentuado do extrato de folhas de oliveira. Pode-se concluir que o tratamento com extrato de folhas de oliveira (OLE) pode ser eficaz na diminuição da lesão hepática e do estresse oxidativo induzido pela overdose de paracetamol em ratos albinos machos

Animals , Rats , Plant Extracts/pharmacology , Olea , Hepatoprotector Drugs , Chemical and Drug Induced Liver Injury/prevention & control , Acetaminophen/toxicity , Rats, Inbred Strains , Plant Extracts/chemistry , Random Allocation , Oxidants , Rats, Wistar , Plant Leaves , Oxidative Stress/drug effects , Hepatocytes/drug effects , Liver/pathology , Antioxidants/pharmacology