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1.
Leg Med (Tokyo) ; 47: 101740, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32634765

RESUMO

Hepatotoxicity from paracetamol/acetaminophen has occasionally been reported at lower than expected doses. As herbal preparations may interact with pharmaceutical drugs the following in vitro study was undertaken to determine whether the toxic effects of paracetamol on liver cell growth in culture would be exacerbated by the addition of psoralen, a furanocoumarin compound that is present in Psoralea corylifolia, a common Chinese herb. The following study utilising a liver carcinoma cell line (HepG2) showed that Psoralea corylifolia was significantly toxic from 0.3 mg/ml to 5 mg/ml (p < 0.05), whereas paracetamol was not toxic below 50 mM (p = 0.0026). Interactions between previously non-toxic levels of 0.1 mg/ml of Psoralea corylifolia and increasing concentrations of paracetamol (0-50 mM), however, were observed, with a significant increase in toxicity compared to paracetamol alone (30% cell death vs. 72% cell death with Psoralea corylifolia). A significant synergistic interaction was observed at 40 mM paracetamol with 0.1 mg/ml of Psoralea (p = 0.038). This study has, therefore, shown significantly increased hepatotoxicity in cell cultures exposed to paracetamol when herbal compounds containing furanocoumarins were added. Fulminant acute liver failure occurring after the ingestion of low doses of paracetamol may not, therefore, always be due to an occult idiosyncratic response to paracetamol, but instead possibly to the combined effects of paracetamol and herbal preparations. Given the widespread use of both paracetamol and herbal preparations this possibility should be considered in cases of unexplained hepatic necrosis and liver failure that present for medicolegal investigation.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Ficusina/toxicidade , Fígado/patologia , Morte Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Sinergismo Farmacológico , Ficusina/isolamento & purificação , Células Hep G2 , Humanos , Falência Hepática/induzido quimicamente , Necrose/induzido quimicamente , Psoralea/química
2.
Environ Toxicol ; 35(11): 1251-1259, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32677766

RESUMO

Isatidis Folium (IF) has been clinically combined with acetaminophen (APAP), but the rationality of combinational therapy is still ambiguous. In the present study, the protective effect and related mechanism of IF on APAP-induced hepatotoxicity were evaluated. Hepatic histopathology and blood biochemistry investigations clearly demonstrated that IF could restore APAP-induced hepatotoxicity. Liver distribution study indicated that the hepatoprotective effect of IF on APAP is attributed to the reduction of N-acetyl-p-benzoquinone imine (NAPQI) in liver, which is a known hepatotoxic metabolite of APAP. Further study suggested the reduction is not via decreasing the generation of NAPQI through inhibiting the enzyme activities of CYP 1A2, 2E1, and 3A4 but via accelerating the transformation of NAPQI to NAPQI-GSH by promoting GSH and decreasing GSSG contents in liver. Furthermore, IF significantly enhanced the hepatic activities of GSH-associated enzymes in APAP-treated mice. In summary, IF could alleviate APAP-induced hepatotoxicity by reducing the content of NAPQI via enhancing the level of GSH and the followed generation of NAPQI-GSH which might be ascribed to the upregulation of GSH-associated enzymes.


Assuntos
Acetaminofen/toxicidade , Antioxidantes/metabolismo , Extratos Vegetais/farmacologia , Acetaminofen/metabolismo , Animais , Benzoquinonas , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Citocromo P-450 CYP1A2 , Glutationa/metabolismo , Iminas , Fígado/efeitos dos fármacos , Masculino , Camundongos , Folhas de Planta
3.
PLoS Comput Biol ; 16(6): e1007622, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32484845

RESUMO

Interpretations of elevated blood levels of alanine aminotransferase (ALT) for drug-induced liver injury often assume that the biomarker is released passively from dying cells. However, the mechanisms driving that release have not been explored experimentally. The usefulness of ALT and related biomarkers will improve by developing mechanism-based explanations of elevated levels that can be expanded and elaborated incrementally. We provide the means to challenge the ability of closely related model mechanisms to generate patterns of simulated hepatic injury and ALT release that scale (or not) to be quantitatively similar to the wet-lab validation targets, which are elevated plasma ALT values following acetaminophen (APAP) exposure in mice. We build on a published model mechanism that helps explain the generation of characteristic spatiotemporal features of APAP hepatotoxicity within hepatic lobules. Discrete event and agent-oriented software methods are most prominent. We instantiate and leverage a small constellation of concrete model mechanisms. Their details during execution help bring into focus ways in which particular sources of uncertainty become entangled with cause-effect details within and across several levels. We scale ALT amounts in virtual mice directly to target plasma ALT values in individual mice. A virtual experiment comprises a set of Monte Carlo simulations. We challenge the sufficiency of four potentially explanatory theories for ALT release. The first of the tested model theories failed to achieve the initial validation target, but each of the three others succeeded. Results for one of the three model mechanisms matched all target ALT values quantitatively. It explains how ALT externalization is the combined consequence of lobular-location-dependent drug-induced cellular damage and hepatocyte death. Falsification of one (or more) of the model mechanisms provides new knowledge and incrementally shrinks the constellation of model mechanisms. The modularity and biomimicry of our explanatory models enable seamless transition from mice to humans.


Assuntos
Alanina Transaminase/sangue , Biomarcadores/sangue , Hepatócitos/efeitos dos fármacos , Necrose , Acetaminofen/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas , Biologia Computacional , Simulação por Computador , Hepatócitos/enzimologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos , Método de Monte Carlo , Software
4.
Toxicology ; 441: 152493, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32479839

RESUMO

Early diagnosis of liver injuries caused by drugs or occupational exposures is necessary to enable effective treatments and prevent liver failure. Whereas histopathology remains the gold standard for assessing hepatotoxicity in animals, plasma aminotransferase levels are the primary measures for monitoring liver dysfunction in humans. In this study, using Sprague Dawley rats, we investigated whether integrated analyses of transcriptomic and metabolomic data with genome-scale metabolic models (GSMs) could identify early indicators of injury and provide new insights into the mechanisms of hepatotoxicity. We obtained concurrent measurements of gene-expression changes in the liver and kidneys, and expression changes along with metabolic profiles in the plasma and urine, from rats 5 or 10 h after exposing them to one of two classical hepatotoxicants, acetaminophen (2 g/kg) or bromobenzene (0.4 g/kg). Global multivariate analyses revealed that gene-expression changes in the liver and metabolic profiles in the plasma and urine of toxicant-treated animals differed from those of controls, even at time points much earlier than changes detected by conventional markers of liver injury. Furthermore, clustering analysis revealed that both the gene-expression changes in the liver and the metabolic profiles in the plasma induced by the two hepatotoxicants were highly correlated, indicating commonalities in the liver toxicity response. Systematic GSM-based analyses yielded metabolites associated with the mechanisms of toxicity and identified several lipid and amino acid metabolism pathways that were activated by both toxicants and those uniquely activated by each. Our findings suggest that several metabolite alterations, which are strongly associated with the mechanisms of toxicity and occur within injury-specific pathways (e.g., of bile acid and fatty acid metabolism), could be targeted and clinically assessed for their potential as early indicators of liver damage.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/sangue , Acetaminofen/toxicidade , Animais , Biomarcadores/sangue , Biomarcadores/urina , Bromobenzenos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/urina , Perfilação da Expressão Gênica , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Metabolômica , Ratos Sprague-Dawley
5.
Int. j. morphol ; 38(3): 585-591, June 2020. graf
Artigo em Inglês | LILACS | ID: biblio-1098291

RESUMO

Acetaminophen (also called paracetamol, or APAP) induced nephrotoxicity is reported after accidental or intentional ingestion of an overdose of the drug. Renal tubular ultrastructural alterations induced by APAP overdose associated with the induction of biomarkers of kidney injury have not been investigated before. Also, we investigated whether the combined polyphenolic anti-inflammatory and antioxidants agents, resveratrol (RES) and quercetin (QUR) can protect against APAP-induced acute kidney injury. The model group of rats received a single dose of APAP (2 g/kg), whereas the protective group of rats was pre-treated for 7 days with combined doses of RES (30 mg/kg) and QUR (50 mg/kg) before being given a single dose of APAP. All rats were then sacrificed one day post APAP ingestion. Harvested kidney tissues were prepared for transmission electron microscopy (TEM) staining and blood samples were assayed for urea, creatinine, and biomarkers of inflammation and oxidative stress. TEM images and blood chemistry analysis showed that APAP overdose induced kidney damage as demonstrated by substantial alterations to the proximal convoluted tubule ultrastructure, and a significant (p<0.05) increase in urea, creatinine, tumor necrosis factor-alpha (TNF-a), and malondialdehyde (MDA) blood levels, which were protected by RES+QUR. These findings indicate that APAP induces alterations to the renal tubular ultrastructure, which is inhibited by resveratrol plus quercetin, which also decreases blood levels of kidney injury biomarkers.


El objetivo de este trabajo fue estudiar la nefrotoxicidad inducida por acetaminofeno (también llamado paracetamol o APAP) después de la ingestión accidental o intencional de una sobredosis de la droga. Las alteraciones ultraestructurales tubulares renales inducidas por sobredosis de APAP asociadas con la inducción de biomarcadores de daño renal no se han investigado. Además, estudiamos si los agentes combinados antiinflamatorios y antioxidantes polifenólicos, el resveratrol (RES) y la quercetina (QUR) pueden proteger contra la lesión renal aguda inducida por APAP. El grupo modelo de ratas recibió una dosis única de APAP (2 g / kg), mientras que el grupo protector de ratas se trató previamente durante 7 días con dosis combinadas de RES (30 mg / kg) y QUR (50 mg / kg) antes de recibir una dosis única de APAP. Todas las ratas se sacrificaron un día después de la ingestión de APAP. Los tejidos renales fueron preparados para el análisis a través de la microscopía electrónica de transmisión (MET). En las muestras de sangre se determinaron la urea, creatinina y los biomarcadores de inflamación y estrés oxidativo. Las imágenes MET y el análisis químico de la sangre mostraron que la sobredosis de APAP inducía daño renal, como lo demuestran las alteraciones sustanciales en la ultraestructura del túbulo contorneado proximal, y además, de un aumento significativo (p <0,05) de la urea, creatinina, factor de necrosis tumoral alfa y niveles sanguíneos de malondialdehído, protegidos por RES + QUR. Estos hallazgos indican que APAP induce alteraciones en la ultraestructura tubular renal, inhibida por el resveratrol más quercetina, que también disminuye los niveles sanguíneos de biomarcadores de daño renal.


Assuntos
Animais , Ratos , Quercetina/administração & dosagem , Resveratrol/administração & dosagem , Túbulos Renais/efeitos dos fármacos , Acetaminofen/toxicidade , Quercetina/farmacologia , Ureia/sangue , Ratos Sprague-Dawley , Creatinina/sangue , Microscopia Eletrônica de Transmissão , Modelos Animais de Doenças , Overdose de Drogas , Resveratrol/farmacologia , Túbulos Renais/patologia , Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem
6.
Nucleic Acids Res ; 48(W1): W455-W462, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32421831

RESUMO

In the past few decades, major initiatives have been launched around the world to address chemical safety testing. These efforts aim to innovate and improve the efficacy of existing methods with the long-term goal of developing new risk assessment paradigms. The transcriptomic and toxicological profiling of mammalian cells has resulted in the creation of multiple toxicogenomic datasets and corresponding tools for analysis. To enable easy access and analysis of these valuable toxicogenomic data, we have developed ToxicoDB (toxicodb.ca), a free and open cloud-based platform integrating data from large in vitro toxicogenomic studies, including gene expression profiles of primary human and rat hepatocytes treated with 231 potential toxicants. To efficiently mine these complex toxicogenomic data, ToxicoDB provides users with harmonized chemical annotations, time- and dose-dependent plots of compounds across datasets, as well as the toxicity-related pathway analysis. The data in ToxicoDB have been generated using our open-source R package, ToxicoGx (github.com/bhklab/ToxicoGx). Altogether, ToxicoDB provides a streamlined process for mining highly organized, curated, and accessible toxicogenomic data that can be ultimately applied to preclinical toxicity studies and further our understanding of adverse outcomes.


Assuntos
Bases de Dados Genéticas , Software , Toxicogenética/métodos , Acetaminofen/toxicidade , Animais , Gráficos por Computador , DNA/biossíntese , Mineração de Dados , Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Inibidores da Síntese de Ácido Nucleico/toxicidade , Ratos
7.
J Toxicol Sci ; 45(5): 245-260, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32404557

RESUMO

Some patients encounter hepatotoxicity after repeated acetaminophen (APAP) dosing even at therapeutic doses. In the present study, we focused on the diabetic state as one of the suggested risk factors of drug-induced liver injury in humans and investigated the contribution of accelerated gluconeogenesis to the susceptibility to APAP-induced hepatotoxicity using an animal model of type 2 diabetes patients. Sprague-Dawley (SD) rats and spontaneously diabetic torii (SDT) rats were each given APAP at 0 mg/kg, 300 and 500 mg/kg for 35 days by oral gavage. Plasma and urinary glutathione-related metabolites, liver function parameters, and hepatic glutathione levels were compared between the non-APAP-treated SDT and SD rats and between the APAP-treated SDT and SD rats. Hepatic function parameters were not increased at either dose level in the APAP-treated SD rats, but were increased at both dose levels in the APAP-treated SDT rats. Increases in hepatic glutathione levels attributable to the treatment of APAP were noted only in the APAP-treated SD rats. There were differences in the profiles of plasma and urinary glutathione-related metabolites between the non-APAP-treated SD and SDT rats and the plasma/urinary endogenous metabolite profile after treatment with APAP in the SDT rats indicated that hepatic glutathione synthesis was decreased due to accelerated gluconeogenesis. In conclusion, SDT rats were more sensitive to APAP-induced chronic hepatotoxicity than SD rats and the high susceptibility of SDT rats was considered to be attributable to lowered hepatic glutathione levels induced by accelerated gluconeogenesis.


Assuntos
Acetaminofen/efeitos adversos , Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Diabetes Mellitus Tipo 2/complicações , Fígado/efeitos dos fármacos , Acetaminofen/administração & dosagem , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Animais de Doenças , Gluconeogênese/fisiologia , Glutationa/metabolismo , Fígado/metabolismo , Masculino , Ratos Sprague-Dawley , Fatores de Risco
8.
Aquat Toxicol ; 224: 105499, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32416570

RESUMO

Pharmaceutical substances are ubiquitous in the aquatic environment and their concentration levels typically range from ng/L up to several µg/L. Furthermore, as those compounds are designed to be highly biologically active, assessing their impacts on non-target organisms is important. Here, we conducted a mesocosm experiment testing a mixture of five pharmaceuticals (diclofenac, carbamazepine, irbesartan, acetaminophen and naproxen) on fish, three-spined stickleback (Gasterosteus aculeatus). The mixture concentration levels were chosen on the basis of the contamination of the Meuse river in Belgium which had been measured previously during a monitoring campaign undertaken in 2015 and 2016. Three nominal mixture concentration levels were tested: the lowest concentration level mixture was composed by environmentally-relevant concentrations that approximate average realistic values for each pharmaceuticals (Mx1); the two other levels were 10 and 100 times these concentrations. Although no impact on stickleback prey was observed, the mixture significantly impaired the survival of female fish introduced in the mesocosms at the highest treatment level without causing other major differences on fish population structure. Impacts on condition factors of adults and juveniles were also observed at both individual and population levels. Using a modelling approach with an individual-based model coupled to a bioenergetic model (DEB-IBM), we concluded that chronic exposure to environmentally-relevant concentrations of five pharmaceuticals often detected in the rivers did not appear to strongly affect the three-spined stickleback populations. Mechanisms of population regulation may have counteracted the mixture impacts in the mesocosms.


Assuntos
Preparações Farmacêuticas/análise , Rios/química , Smegmamorpha/crescimento & desenvolvimento , Poluentes Químicos da Água/toxicidade , Acetaminofen/análise , Acetaminofen/toxicidade , Animais , Bélgica , Carbamazepina/análise , Carbamazepina/toxicidade , Diclofenaco/análise , Diclofenaco/toxicidade , Feminino , Modelos Teóricos , Naproxeno/análise , Naproxeno/toxicidade , Dinâmica Populacional , Smegmamorpha/fisiologia , Poluentes Químicos da Água/análise
9.
Life Sci ; 255: 117832, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32450164

RESUMO

AIMS: N-Acetylcysteine (NAC) is an effective antidote for the treatment of acetaminophen (APAP) poisoning; however, due to its low stability and bioavailability, repeated dosing of NAC is needed. This study investigated the therapeutic efficacy of NAC by niosomal carriers. MATERIALS AND METHODS: Niosomes were synthesized using surface active agents film hydration method and their physicochemical properties were characterized. In the in vivo study, in addition to control group, male rats were divided in different groups and challenged with an oral dose of APAP (2000 mg/kg); 4 h later, rats were administered normal saline, empty niosome (NIO), NAC (25 mg/kg) and NAC-loaded niosome (NAC-NIO) respectively, and sacrificed 48 h post-APAP overdose. KEY FINDINGS: The particle size and zeta potential of NAC-NIO were 242.3 ± 18.5 nm and -23.9 ± 1.6 mV. The loading and encapsulation efficiency of niosomes were 1.22% ± 0.02% and 26.76% ± 6.02%. APAP administration leads to hepatic damage as evidenced by increases in serum hepatic enzyme levels and tissue levels of nitric oxide and lipid peroxidation as well as decreases in hepatic levels of reduced glutathione, catalase, superoxide dismutase, and glutathione peroxidase. Treatment of rats with NIO-NAC was remarkably more effective than NAC in improving biochemical changes such as serum hepatic aminotransferases. These findings were correlated well to the histopathological experiments. SIGNIFICANCE: Our results suggest that NAC when delivered as a niosomal structure, is potentially more effective than NAC standard, in improving APAP-induced hepatotoxicity.


Assuntos
Acetaminofen/toxicidade , Acetilcisteína/administração & dosagem , Analgésicos não Entorpecentes/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Nanopartículas , Acetaminofen/administração & dosagem , Acetilcisteína/farmacologia , Administração Oral , Analgésicos não Entorpecentes/administração & dosagem , Animais , Antídotos/administração & dosagem , Antídotos/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Sistemas de Liberação de Medicamentos , Lipossomos , Masculino , Tamanho da Partícula , Polietilenoglicóis/química , Ratos , Ratos Wistar , Tensoativos/química
10.
Toxicol Appl Pharmacol ; 396: 114982, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32240663

RESUMO

Oxidative stress contributes to acetaminophen (APAP) hepatotoxicity. Since lipid peroxidation produces reactive aldehydes, we investigated whether activation of mitochondrial aldehyde dehydrogenase-2 (ALDH2) with Alda-1 decreases liver injury after APAP. Male C57BL/6 mice fasted overnight received Alda-1 (20 mg/kg, i.p.) or vehicle 30 min before APAP (300 mg/kg, i.p.). Blood and livers were collected 2 or 24 h after APAP. Intravital multiphoton microscopy of rhodamine 123 (Rh123) and propidium iodide (PI) fluorescence was conducted 6 h after APAP administration to detect mitochondrial polarization status and cell death. 4-Hydroxynonenal protein adducts were present in 0.1% of tissue area without APAP treatment but increased to 7% 2 h after APAP treatment, which Alda-1 blunted to 1%. Serum alanine and aspartate aminotransferases increased to 7594 and 9768 U/L at 24 h respectively, which decreased ≥72% by Alda-1. Alda-1 also decreased centrilobular necrosis at 24 h after APAP from 47% of lobular areas to 21%. N-acetyl-p-benzoquinone imine protein adduct formation and c-Jun-N-terminal kinase phosphorylation increased after APAP as expected, but Alda-1 did not alter these changes. Without APAP, no mitochondrial depolarization was detected by intravital microscopy. At 6 h after APAP, 62% of tissue area showed depolarization, which decreased to 33.5% with Alda-1. Cell death as detected by PI labeling increased from 0 to 6.8 cells per 30× field 6 h after APAP, which decreased to 0.6 cells by Alda-1. In conclusion, aldehydes are important mediators of APAP hepatotoxicity. Accelerated aldehyde degradation by ALDH2 activation with Alda-1 decreases APAP hepatotoxicity by protection against mitochondrial dysfunction.


Assuntos
Acetaminofen/toxicidade , Aldeído-Desidrogenase Mitocondrial/metabolismo , Analgésicos não Entorpecentes/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Benzamidas/farmacologia , Benzodioxóis/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Ativação Enzimática , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência por Excitação Multifotônica , Mitocôndrias Hepáticas/metabolismo
11.
Toxicology ; 439: 152464, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32315716

RESUMO

Mitochondrial injury and depolarization are primary events in acetaminophen hepatotoxicity. Previous studies have shown that restoration of mitochondrial function in surviving hepatocytes, which is critical to recovery, is at least partially accomplished via biogenesis of new mitochondria. However, other studies indicate that mitochondria also have the potential to spontaneously repolarize. Although repolarization was previously observed only at a sub-hepatotoxic dose of acetaminophen, we postulated that mitochondrial repolarization in hepatocytes outside the centrilobular regions of necrosis might contribute to recovery of mitochondrial function following acetaminophen-induced injury. Our studies utilized longitudinal intravital microscopy of millimeter-scale regions of the mouse liver to characterize the spatio-temporal relationship between mitochondrial polarization and necrosis early in acetaminophen-induced liver injury. Treatment of male C57BL/6J mice with a single intraperitoneal 250 mg/kg dose of acetaminophen resulted in hepatotoxicity that was apparent histologically within 2 h of treatment, leading to 20 and 60-fold increases in serum aspartate aminotransferase and alanine aminotransferase, respectively, within 6 h. Intravital microscopy of the livers of mice injected with rhodamine123, TexasRed-dextran, propidium iodide and Hoechst 33342 detected centrilobular foci of necrosis within extended regions of mitochondrial depolarization within 2 h of acetaminophen treatment. Although regions of necrosis were more apparent 6 h after acetaminophen treatment, the vast majority of hepatocytes with depolarized mitochondria did not progress to necrosis, but rather recovered mitochondrial polarization within 6 h. Recovery of mitochondrial function following acetaminophen hepatotoxicity thus involves not only biogenesis of new mitochondria, but also repolarization of existing mitochondria. These studies also revealed a spatial distribution of necrosis and mitochondrial depolarization whose single-cell granularity is inconsistent with the hypothesis that communication between neighboring cells plays an important role in the propagation of necrosis during the early stages of APAP hepatotoxicity. Small islands of healthy, intact cells were frequently found surrounded by necrotic cells, and small islands of necrotic cells were frequently found surrounded by healthy, intact cells. Time-series studies demonstrated that these "islands", consisting in some cases of single cells, are persistent; over a period of hours, injury does not spread from individual necrotic cells to their neighbors.


Assuntos
Acetaminofen/toxicidade , Analgésicos não Entorpecentes/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/patologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Necrose/patologia
12.
Artigo em Inglês | MEDLINE | ID: mdl-32300985

RESUMO

Paracetamol (APAP) is a widely used non-steroidal anti-inflammatory drug and has been frequently detected in aquatic environment. However, limited information is provided about the toxic effects and detoxification mechanism of APAP in aquatic invertebrates. In the present study, the change of life traits of Daphnia magna (e.g., body length, growth rate and reproduction) was investigated under the chronic APAP exposure (0-5000 µg/L) for 21 day, and the effects of APAP on the expression of the detoxification- and reproduction-related genes including HR96, CYP360A8, CYP314, MRP4, P-gp, EcR and Vtg in the acute exposure (up to 96 h) were also determined. Results showed that the molting frequency, days to the first brood and days to the first egg production of D. magna were affected under the 50 µg/L concentration of APAP in the chronic exposure test. In the acute test, the transcriptional expression of HR96 was up-regulated under APAP exposure for 24 and 48 h. Similar performances were also observed in the expression of CYP360A8, CYP314, MRP4 and P-gp. However, with exposure time extended to 96 h, the induction of HR96 decreased or even reversed in some cases. It may indicate that the defense system in Daphnia is activated for a short time of exposure or becomes adaptive after longer term of exposure. APAP exposure also affected reproduction-related genes expression, which was related to the exposure time and concentration of APAP. In summary, APAP significantly affected the expression of genes associated with detoxification metabolism and altered some physiological parameters in D. magna.


Assuntos
Acetaminofen/toxicidade , Daphnia/fisiologia , Poluentes Químicos da Água/toxicidade , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Inativação Metabólica , Muda/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Testes de Toxicidade Crônica
13.
Zhongguo Zhong Yao Za Zhi ; 45(6): 1433-1439, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32281358

RESUMO

The aim of this study was to observe the protective effect of water extract from Sabia parviflora on mice with acute liver injury induced by acetaminophen, and investigate its possible mechanism. Fifty-eight Kunming mice were divided into 6 groups, 8 in the normal group, 10 in the model group, 10 in the biphenyl diester group, and 10 each in the low, medium and high dose groups. After adaptive feeding for one week, the mice in normal group were intragastrically administered with an equal volume of 0.5% sodium carboxymethylcellulose sodium(CMC-Na), and the mice in other groups were intragastrically administered with corresponding drugs at 20 mL·kg~(-1) once a day. Then acetaminophen(200 mg·kg~(-1)) was administered after the above drug administration except the normal group. The behavior and signs of the experimental animals were observed every day and the samples were taken for experiments on the next day of the final administration. The liver mass and mass index were calculated. The blood was collected from the abdominal aorta and centrifuged to obtain the serum for detecting aspartate aminotransferase(AST) activity and alanine aminotransferase(ALT) activity. The liver tissue homogenate was used to detect superoxide dismutase(SOD) activity, glutathione(glutathione, r-glutamyl cysteingl+glycine, GSH) activity and malondialdehyde(MDA) content. Liver tissue was analyzed for histological analysis. The results showed that S. parviflora could alleviate the lipid peroxidation damage in the liver caused by acetaminophen, reduce the ALT and AST activities in serum, increase the levels of SOD and GSH in liver tissue, decrease the content of MDA in liver tissue, and inhibit the apoptosis. S. parviflora could also improve the live histopathological profile, protect liver cells and restore liver function. Among them, the high dose had the most significant effect and showed dose-effect relationship. This study indicated that S. parviflora had a significant protective effect on acetaminophen-induced liver injury in mice, and its mechanism may be related to its anti-oxidation effect and inhi-bitory effect on apoptosis.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Fígado/enzimologia , Malondialdeído/análise , Camundongos , Estresse Oxidativo , Superóxido Dismutase/metabolismo
14.
Food Chem Toxicol ; 138: 111240, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32145352

RESUMO

Acetaminophen (APAP) is a widely used analgesic drug, which can cause severe liver injury after an overdose. The intracellular signaling mechanisms of APAP-induced cell death such as reactive metabolite formation, mitochondrial dysfunction and nuclear DNA fragmentation have been extensively studied. Hepatocyte necrosis releases damage-associated molecular patterns (DAMPs) which activate cytokine and chemokine formation in macrophages. These signals activate and recruit neutrophils, monocytes and other leukocytes into the liver. While this sterile inflammatory response removes necrotic cell debris and promotes tissue repair, the capability of leukocytes to also cause tissue injury makes this a controversial topic. This review summarizes the literature on the role of various DAMPs, cytokines and chemokines, and the pathophysiological function of Kupffer cells, neutrophils, monocytes and monocyte-derived macrophages, and NK and NKT cells during APAP hepatotoxicity. Careful evaluation of results and experimental designs of studies dealing with the inflammatory response after APAP toxicity provide very limited evidence for aggravation of liver injury but support of the hypothesis that these leukocytes promote tissue repair. In addition, many cytokines and chemokines modulate tissue injury by affecting the intracellular signaling events of cell death rather than toxicity of leukocytes. Reasons for the controversial results in this area are also discussed.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/fisiopatologia , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Animais , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Imunidade Inata , Inflamação/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Fígado/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Necrose/induzido quimicamente , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia
15.
Chin J Nat Med ; 18(2): 103-113, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32172946

RESUMO

We investigated the liver protective activity of dandelion polyphenols (DP) against acetaminophen (APAP; Paracetamol)-induced hepatotoxicity. Mice were acclimated for 1 week and randomly divided into the following groups (n = 9 per group): Control, APAP, APAP + DP (100 mg·kg-1), APAP + DP (200 mg·kg-1), and APAP + DP (400 mg·kg-1) groups. Mice were pretreated with DP (100, 200, and 400 mg·kg-1) by oral gavage for 7 d before being treated with 350 mg·kg-1 APAP for 24 h to induced hepatotoxicity. Severe liver injury was observed, and hepatotoxicity was analyzed after 24 h by evaluation of biochemical markers, protein expressions levels, and liver histopathology. Pretreatment with DP was able to restore serum liver characteristics (aspartate transaminase, AST; alanine aminotransferase, ALT; alkaline phosphatase, AKP), improve redox imbalance (superoxide dismutase, SOD; glutathione, GSH; malondialdehyde, MDA), and decrease inflammatory factors (tumor necrosis factor-α, TNF-α; interleukin-1ß, IL-1ß). Pretreatment with DP also significantly inhibited the expression levels of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, DP pretreatment could inhibit the apoptosis of liver cells caused by APAP through up-regulation of Bcl-2 and down-regulation of Bax and caspase-9 protein. DP also down-regulated p-JNK protein expression levels to inhibit APAP-induced mitochondrial oxidative stress and up-regulated the expression of Nrf-2 and its target gene HO-1. The histopathological staining demonstrated that DP pretreatment could inhibit APAP-induced hepatocyte infiltration, congestion, and necrosis. Our results demonstrate that DP pretreatment could protect against APAP-induced hepatic injury by activating the Nrf-2/HO-1 pathway and inhibition of the intrinsic apoptosis pathway.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Taraxacum/química , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/sangue , Modelos Animais de Doenças , Heme Oxigenase-1/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos
16.
J Toxicol Sci ; 45(3): 151-162, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32147638

RESUMO

Information on the safety of chemical substances in patients with various preexisting conditions remains limited. Acetaminophen was added to the basal diet at 0, 80, 253, 800, 2530, or 8000 ppm and administered to type 2 diabetes mellitus rats (GK/Jcl) and the control male rats (Wistar) for 13 weeks. Both strains treated with 8000 ppm acetaminophen (561.4 and 567.7 mg/kg body weight/day, GK/Jcl and Wistar rats, respectively) showed decreased levels of red blood cell counts, blood urea nitrogen, creatinine, and total bilirubin compared to those of non-treated rats. Treatment with 8000 ppm of acetaminophen reduced the blood glucose and hemoglobin A1c levels of GK/Jcl rats. An increase in the relative weights of the kidneys and liver, and a decrease in the weight of the salivary glands were observed in both GK/Jcl and Wistar rats treated with 8000 ppm acetaminophen relative to those of non-treated control rats. Microscopically, both strains treated with 2530 (174.3 and 164.2 mg/kg body weight/day, GK/Jcl and Wistar rats, respectively) or 8000 ppm acetaminophen showed hepatocellular hypertrophy and degenerative lesions in the salivary glands, whereas similar lesions were not observed in non-treated rats. In conclusion, the no-observed-adverse-effect-level of acetaminophen was 800 ppm in both diabetic and control rats.


Assuntos
Acetaminofen/toxicidade , Diabetes Mellitus Tipo 2/fisiopatologia , Nível de Efeito Adverso não Observado , Animais , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Hipertrofia , Masculino , Ratos Wistar
17.
Arterioscler Thromb Vasc Biol ; 40(5): 1207-1219, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32188278

RESUMO

OBJECTIVE: Intravenous acetaminophen/paracetamol (APAP) is well documented to cause hypotension. Since the patients receiving intravenous APAP are usually critically ill, any severe hemodynamic changes, as with those associated with APAP, can be life-threatening. The mechanism underlying this dangerous iatrogenic effect of APAP was unknown. Approach and Results: Here, we show that intravenous APAP caused transient hypotension in rats, which was attenuated by the Kv7 channel blocker, linopirdine. APAP metabolite N-acetyl-p-benzoquinone imine caused vasodilatation of rat mesenteric arteries ex vivo. This vasodilatation was sensitive to linopirdine and also the calcitonin gene-related peptide antagonist, BIBN 4096. Further investigation revealed N-acetyl-p-benzoquinone imine stimulates calcitonin gene-related peptide release from perivascular nerves, causing a cAMP-dependent activation of Kv7 channels. We also show that N-acetyl-p-benzoquinone imine enhances Kv7.4 and Kv7.5 channels overexpressed in oocytes, suggesting that it can activate Kv7.4 and Kv7.5 channels directly, to elicit vasodilatation. CONCLUSIONS: Direct and indirect activation of Kv7 channels by the APAP metabolite N-acetyl-p-benzoquinone imine decreases arterial tone, which can lead to a drop in blood pressure. Our findings provide a molecular mechanism and potential preventive intervention for the clinical phenomenon of intravenous APAP-dependent transient hypotension.


Assuntos
Acetaminofen/toxicidade , Pressão Sanguínea/efeitos dos fármacos , Hipotensão/induzido quimicamente , Canais de Potássio KCNQ/agonistas , Artérias Mesentéricas/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Acetaminofen/metabolismo , Animais , Benzoquinonas , Hipotensão/metabolismo , Hipotensão/fisiopatologia , Iminas , Canais de Potássio KCNQ/genética , Canais de Potássio KCNQ/metabolismo , Masculino , Potenciais da Membrana , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Ratos Wistar , Transdução de Sinais , Xenopus laevis
18.
Genes Cells ; 25(4): 257-269, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32012396

RESUMO

Most physiological changes follow a daily cycle in animals because their circadian rhythm is adjusted to and synchronized with sunlight. In particular, the circadian rhythm affects liver functions, including pharmacokinetics and metabolism. The influence of circadian rhythm has not been included in hepatotoxicity assays used in drug discovery and development. In this study, the contribution of circadian rhythm was investigated in acetaminophen-induced hepatotoxicity in mice and primary cultured hepatocytes. Hepatotoxicity was induced via the intraperitoneal administration of acetaminophen to a greater extent at night than during the day in mice. The sensitivity of acetaminophen-induced hepatotoxicity was consistent with the expression levels of acetaminophen-metabolizing enzyme and circadian genes. The host-derived circadian rhythm was still evident in the primary cultured hepatocytes within a day after their isolation from the liver. Primary cultured hepatocytes isolated at night were significantly more sensitive to acetaminophen than those isolated during the day. The sensitivity toward acetaminophen-induced hepatotoxicity depended on the circadian rhythm of the expression of acetaminophen-metabolizing genes and intracellular glutathione levels in primary cultured hepatocytes. These results obtained from cultured cells correspond to those in mice, suggesting that the timing of hepatocyte isolation is important when investigating drug metabolism and toxicity tests in culture.


Assuntos
Acetaminofen/toxicidade , Separação Celular , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Ritmo Circadiano , Hepatócitos/efeitos dos fármacos , Acetaminofen/administração & dosagem , Animais , Células Cultivadas , Hepatócitos/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Fatores de Tempo
19.
Toxicol Appl Pharmacol ; 392: 114930, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32109512

RESUMO

Acetaminophen (APAP) overdose causes hepatotoxicity involving mitochondrial dysfunction. Previous studies showed that translocation of Fe2+ from lysosomes into mitochondria by the mitochondrial Ca2+ uniporter (MCU) promotes the mitochondrial permeability transition (MPT) after APAP. Here, our Aim was to assess protection by iron chelation and MCU inhibition against APAP hepatotoxicity in mice. C57BL/6 mice and hepatocytes were administered toxic doses of APAP with and without starch-desferal (an iron chelator), minocycline (MCU inhibitor), or N-acetylcysteine (NAC). In mice, starch-desferal and minocycline pretreatment decreased ALT and liver necrosis after APAP by >60%. At 24 h after APAP, loss of fluorescence of mitochondrial rhodamine 123 occurred in pericentral hepatocytes often accompanied by propidium iodide labeling, indicating mitochondrial depolarization and cell death. Starch-desferal and minocycline pretreatment decreased mitochondrial depolarization and cell death by more than half. In cultured hepatocytes, cell killing at 10 h after APAP decreased from 83% to 49%, 35% and 27%, respectively, by 1 h posttreatment with minocycline, NAC, and minocycline plus NAC. With 4 h posttreatment in vivo, minocycline and minocycline plus NAC decreased ALT and necrosis by ~20% and ~50%, respectively, but NAC alone was not effective. In conclusion, minocycline and starch-desferal decrease mitochondrial dysfunction and severe liver injury after APAP overdose, suggesting that the MPT is likely triggered by iron uptake into mitochondria through MCU. In vivo, minocycline and minocycline plus NAC posttreatment after APAP protect at later time points than NAC alone, indicating that minocycline has a longer window of efficacy than NAC.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Ferro/metabolismo , Lisossomos/efeitos dos fármacos , Minociclina/farmacologia , Mitocôndrias/metabolismo , Acetaminofen/administração & dosagem , Analgésicos não Entorpecentes/administração & dosagem , Analgésicos não Entorpecentes/toxicidade , Animais , Antibacterianos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Overdose de Drogas , Hepatócitos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
20.
Mol Pharmacol ; 97(4): 278-286, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32029527

RESUMO

Acetaminophen (APAP) is a commonly used over-the-counter drug for its analgesic and antipyretic effects. However, APAP overdose leads to severe APAP-induced liver injury (AILI) and even death as a result of the accumulation of N-acetyl-p-benzoquinone imine, the toxic metabolite of APAP generated by cytochrome P450s (P450s). Long noncoding RNAs HNF1α antisense RNA 1 (HNF1α-AS1) and HNF4α antisense RNA 1 (HNF4α-AS1) are regulatory RNAs involved in the regulation of P450 expression in both mRNA and protein levels. This study aims to determine the impact of HNF1α-AS1 and HNF4α-AS1 on AILI. Small hairpin RNAs were used to knock down HNF1α-AS1 and HNF4α-AS1 in HepaRG cells. Knockdown of these lncRNAs altered APAP-induced cytotoxicity, indicated by MTT and LDH assays. Specifically, HNF1α-AS1 knockdown decreased APAP toxicity with increased cell viability and decreased LDH release, whereas HNF4α-AS1 knockdown exacerbated APAP toxicity, with opposite effects in the MTT and LDH assays. Alterations on gene expression by knockdown of HNF1α-AS1 and HNF4α-AS1 were examined in several APAP metabolic pathways, including CYP1A2, CYP2E1, CYP3A4, UGT1A1, UGT1A9, SULT1A1, GSTP1, and GSTT1. Knockdown of HNF1α-AS1 decreased mRNA expression of CYP1A2, 2E1, and 3A4 by 0.71-fold, 0.35-fold, and 0.31-fold, respectively, whereas knockdown of HNF4α-AS1 induced mRNAs of CYP1A2, 2E1, and 3A4 by 1.3-fold, 1.95-fold, and 1.9-fold, respectively. These changes were also observed in protein levels. Knockdown of HNF1α-AS1 and HNF4α-AS1 had limited effects on the mRNA expression of UGT1A1, UGT1A9, SULT1A1, GSTP1, and GSTT1. Altogether, our study suggests that HNF1α-AS1 and HNF4α-AS1 affected AILI mainly through alterations of P450-mediated APAP biotransformation in HepaRG cells, indicating an important role of the lncRNAs in AILI. SIGNIFICANCE STATEMENT: The current research identified two lncRNAs, hepatocyte nuclear factor 1α antisense RNA 1 and hepatocyte nuclear factor 4α antisense RNA 1, which were able to affect susceptibility of acetaminophen (APAP)-induced liver injury in HepaRG cells, possibly through regulating the expression of APAP-metabolizing cytochrome P450 enzymes. This discovery added new factors, lncRNAs, which can be used to predict cytochrome P450-mediated drug metabolism and drug-induced toxicity.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/genética , Sistema Enzimático do Citocromo P-450/genética , Hepatócitos/efeitos dos fármacos , RNA Longo não Codificante/metabolismo , Acetaminofen/metabolismo , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/patologia , Sistema Enzimático do Citocromo P-450/metabolismo , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Predisposição Genética para Doença , Hepatócitos/patologia , Humanos , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo
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