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1.
J Toxicol Sci ; 45(9): 515-537, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879252

RESUMO

The activities of the transaminases (aminotransferases) alanine aminotransferase and aspartate aminotransferase in the blood (serum or plasma) are widely used as sensitive markers of possible tissue damage and, in particular for liver toxicity. On the other hand, an increase in transaminase activities is not always accompanied by findings suggestive of hepatotoxicity. Transaminases are some of the key enzymes in the gluconeogenesis and glycolysis pathways and exist in many organs and tissues which have high activities of the gluconeogenesis and glycolysis. The activities of transaminases are altered not only in the liver but also in other organs by modification of gluconeogenesis by nutritional or hormonal factors and this phenomenon leads to alteration of transaminase activity in the blood. Drugs, which are considered to directly or secondarily modify gluconeogenesis through lowering blood glucose levels or activating lipid metabolism, such as α-glucosidase inhibitors and fibrates, slightly increase transaminase activities in the blood but there is little evidence that the phenomenon is related to drug-induced liver injury (DILI). This type of elevations can be called pharmacology-related elevation. The pharmacology-related elevation of transaminase activities sometimes makes it difficult to assess precisely the potential hepatotoxicity of new investigational drugs. Considering the characteristic of transaminases, concomitant use of new biomarkers more specific to hepatic injury is needed in the assessment of DILI both in non-clinical and clinical studies. In this review, we will discuss the specificity of transaminases to DILI and future perspectives for transaminases in the estimation of risk of DILI.


Assuntos
Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Gluconeogênese , Glicólise , Humanos , Fígado/metabolismo , Valor Preditivo dos Testes , Risco , Sensibilidade e Especificidade
2.
Ecotoxicol Environ Saf ; 205: 111342, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32971455

RESUMO

Radix aconiti lateralis (Fuzi) is widely used in China as a traditional Chinese medicine for the treatment of asthenia, pain and inflammation. However, its toxic alkaloids often lead to adverse reactions. Currently, most of the toxicity studies on Fuzi are focused on the heart and nervous system, and more comprehensive toxicity studies are needed. In this study, based on the previous reports of Fuzi hepatotoxicity, serum pharmacochemistry and network toxicology were used to screen the potential toxic components of Heishunpian(HSP), a processed product of Fuzi, and to explore the possible mechanism of HSP-induced hepatotoxicity. The results obtained are expressed based on the toxicological evidence chain (TEC). It was found that 22 potential toxic components screened can affect Th17 cell differentiation, Jak-STAT signaling pathway, glutathione metabolism, and other related pathways by regulating AKT1, IL2, F2, GSR, EGFR and other related targets, which induces oxidative stress, metabolic disorders, cell apoptosis, immune response, and excessive release of inflammatory factors, eventually inducing liver damage in rats. This is the first study on HSP-induced hepatotoxicity based on the TEC concept, providing references for further studies on the toxicity mechanism of Fuzi.


Assuntos
Aconitum/química , Alcaloides/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Medicamentos de Ervas Chinesas/toxicidade , Modelos Biológicos , Alcaloides/sangue , Alcaloides/isolamento & purificação , Animais , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , China , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacocinética , Masculino , Medicina Tradicional Chinesa , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
3.
Ecotoxicol Environ Saf ; 203: 110928, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888618

RESUMO

Hexavalent chromium [Cr(VI)] is seriously harmful to ecosystems and living organisms due to its strong toxicity. Role of dynamin-related protein 1 (Drp1) and Drp1-associated mitochondrial fragmentation in mitophagy and cytotoxicity after Cr(VI) exposure has not been clarified so far. We confirmed that Cr(VI) caused mitochondrial fission by up-regulating Drp1 expression and enhancing Drp1 mitochondrial translocation. By applying the intracellular Ca2+ antagonist BAPTA-AM and mitochondrial Ca2+ antagonist Ru360, we demonstrated that Cr(VI)-induced excessive mitochondrial fission was in a Ca2+-Drp1 dependent manner. The administration of Drp1 siRNA significantly suppressed the overactivation of mitophagy in Cr(VI)-induced hepatotoxicity. The specific Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1) blocked the overactive mitophagy and subsequently ameliorated hepatotoxicity caused by Cr(VI) in vivo. We reached the conclusion that Drp1-dependent mitochondrial fission contributes to Cr(VI)-induced mitophagy and hepatotoxicity, which may provide experimental basis for the study of chromium-associated toxicity, especially for the prevention of health damage in chromium-exposed population.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Cromo/toxicidade , Dinaminas/metabolismo , Poluentes Ambientais/toxicidade , Hepatócitos/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Animais , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ecossistema , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , RNA Interferente Pequeno/metabolismo
4.
Ecotoxicol Environ Saf ; 205: 111126, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32823070

RESUMO

Triphenyl phosphate (TPP) has been found in various environmental media and in biota suggesting widespread human exposure. However, there is still insufficient information on the hepatotoxicity mechanisms of health risk exposed to TPP. In this study, TPP could induce human normal liver cell (L02) apoptosis, injury cell ultrastructure and elevate the levels of reactive oxygen species (ROS). The integrated multi-omic (transcriptomic, proteomic, and metabolomic) analysis was used to further investigate the mechanisms. Transcriptomic analysis revealed that TPP exposure markedly affected cell apoptosis, oncogene activation, REDOX homeostasis, DNA damage and repair. Additionally, proteomic analysis found that the related proteins associated with apoptosis, oxidative stress, metabolism and membrane structure were affected. And metabolomic analysis verified that the related metabolic pathways, such as glycolysis, citrate cycle, oxidative phosphorylation, lipid and protein metabolism, were also significantly disrupted. Based on the multi-omic results, a hypothesized network was constructed to discover the key molecular events in response to TPP and illustrate the mechanism of TPP-induced hepatotoxicity in L02 cells. Therefore, molecular responses could be elucidated at multiple biological levels, and multi-omic analysis could provide scientific tools for exploring potential mechanisms of toxicity and chemical risk assessment.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Poluentes Ambientais/toxicidade , Redes e Vias Metabólicas/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Organofosfatos/toxicidade , Transcriptoma/efeitos dos fármacos , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Perfilação da Expressão Gênica , Humanos , Metabolômica , Estresse Oxidativo/efeitos dos fármacos , Proteômica , Espécies Reativas de Oxigênio/metabolismo
5.
J Toxicol Sci ; 45(8): 493-502, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741899

RESUMO

Gefitinib (GEF) is the first selective tyrosine kinase inhibitor of epidermal growth factor receptor. It is associated with the occurrence of clinical drug-induced liver injury. Although GEF is metabolized to chemically reactive metabolites by cytochrome P450 3A and 1A enzymes and then conjugated to glutathione (GSH), whether these reactive metabolites contribute to GEF-induced toxicity remains unknown. In this study, we investigated whether GSH depletion can sensitize mice to liver injury caused by GEF. Male C57BL/6J mice were intraperitoneally pretreated with L-buthionine (S,R)-sulfoximine (BSO) at 700 mg/kg to inhibit GSH synthesis and then orally administered GEF at 500 mg/kg every 24 hr for 4 consecutive days. The coadministration of BSO and GEF increased plasma alanine aminotransferase (ALT) levels to approximately 700 U/L and 1600 U/L at 72 and 96 hr after the first administration, respectively, whereas the increase in plasma ALT levels in mice receiving GEF at 500 mg/kg alone was limited, suggesting that GSH plays a protective role in GEF-induced liver injury. Histological examination showed nuclear karyorrhexis and sporadic single hepatocyte death in the livers of BSO+GEF coadministered mice. In these mice, the hepatic expression levels of heme oxygenase 1 (Hmox1) and metallothionein 2 (Mt2) mRNA, caspase 3/7 enzymatic activity, and the amounts of 2-thiobarbiuric acid reactive substances were significantly increased, suggesting the presence of oxidative stress, which may be associated with hepatocellular death. Together, these results show that oxidative stress as well as the reactive metabolites of GEF are involved in GEF-induced liver injury in GSH-depleted mice.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Gefitinibe/efeitos adversos , Gefitinibe/toxicidade , Glutationa/deficiência , Glutationa/metabolismo , Fígado/metabolismo , Fígado/patologia , Estresse Oxidativo , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/toxicidade , Animais , Butionina Sulfoximina/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocromo P-450 CYP3A/fisiologia , Progressão da Doença , Gefitinibe/metabolismo , Glutationa/fisiologia , Camundongos Endogâmicos C57BL , Inibidores de Proteínas Quinases/metabolismo
6.
Chem Biol Interact ; 329: 109213, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32739323

RESUMO

Phytoestrogens are plant-derived substances with a similar structure to 17-beta-estradiol, which have protective roles in estrogen-dependent diseases. Isoflavones, the most well-known subgroup of phytoestrogens, play protective roles against chemicals-induced liver injuries through several molecular mechanisms. Hepatoprotective effects of isoflavones are, partly, associated with their antioxidant, anti-inflammatory, immunomodulatory, and anti-fibrotic properties. Besides, isoflavones can reduce gut-derived endotoxins, accelerate alcohol metabolism, stimulate detoxification of hepatotoxic chemicals, suppress the bioactivation of these chemicals, inhibit hepatocytes apoptosis, and restore autophagy activity during chemicals-induced liver diseases. This review provides a summary of the molecular mechanisms underlying the hepatoprotective effects of isoflavones. It seems that further studies are needed to investigate the hepatoprotective potential of isoflavones in patients with different stages of chemicals-induced liver injuries.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Isoflavonas/metabolismo , Substâncias Protetoras/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Animais de Doenças , Inflamação/prevenção & controle , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia
7.
Toxicol Lett ; 333: 192-201, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32805337

RESUMO

To gain insights into the benefits of ascorbic acid (AsA) in hepatoprotection, we examined the status of Akr1a-/- (KO) mice, which biosynthesize AsA at about 10% the rate as Akr1a+/+ (WT) mice, in terms of their response to an N-nitrosodiethylamine (NDEA)-induced hepatic injury. The intraperitoneal injection of NDEA (35 mg/kg) started at 4 weeks of age and was performed at weekly intervals thereafter. While the fatality rate was substantial in the KO mice, AsA supplementation (1.5 mg/ml in the drinking water) greatly extended their life-spans. Only two out of 54 KO mice survived to 28 weeks, and both contained approximately an order of magnitude greater number of tumor nodules compared to WT mice or KO mice with AsA supplementation. Histological and biochemical examinations at 20 weeks indicated that AsA potently protected against the hepatotoxic action of NDEA. Interestingly, the AsA levels in the liver were higher in the AsA-supplemented KO mouse groups that had received the NDEA treatment compared to the corresponding control group. While the protein levels of Cyp2e1, an enzyme that plays a major role in the bioactivation of NDEA, had declined to a similar extent among the experimental groups, p-nitrophenol-oxidizing activity was sustained at high levels in the KO mouse livers but AsA supplementation suppressed this activity. These findings confirm that AsA is a potent micronutrient that copes with hepatic injury and cancer development caused by exposure to NDEA in the livers of Akr1a-knockout mice.


Assuntos
Aldeído Redutase/metabolismo , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Carcinogênese/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Dietilnitrosamina/toxicidade , Fígado/efeitos dos fármacos , Aldeído Redutase/genética , Animais , Antioxidantes/metabolismo , Biomarcadores/sangue , Carcinogênese/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise de Sobrevida
8.
Toxicol Lett ; 333: 290-302, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32835833

RESUMO

Triptolide, a major active component of Triptergium wilfordii Hook. f, is used in the treatment of autoimmune disease. However, triptolide is associated with severe adverse reactions, especially hepatotoxicity, which limits its clinical application. To examine the underlying mechanism of triptolide-induced liver injury, a combination of dose- and time-dependent toxic effects, RNA-seq and metabolomics were employed. Triptolide-induced toxicity occurred in a dose- and time-dependent manners and was characterized by apoptosis and not necroptosis. Transcriptomics profiles of the dose-dependent response to triptolide suggested that PI3K/AKT, MAPK, TNFα and p53 signaling pathways were the vital steps in triptolide-induced hepatocyte apoptosis. Metabolomics further revealed that glycerophospholipid, fatty acid, leukotriene, purine and pyrimidine metabolism were the major metabolic alterations after triptolide exposure. Finally, acylcarnitines were identified as potential biomarkers for the early detection of triptolide-induced liver injury.


Assuntos
Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas , Diterpenos/toxicidade , Metaboloma/efeitos dos fármacos , Necroptose/efeitos dos fármacos , Fenantrenos/toxicidade , Transcriptoma/efeitos dos fármacos , Animais , Apoptose/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Relação Dose-Resposta a Droga , Compostos de Epóxi/toxicidade , Perfilação da Expressão Gênica , Metaboloma/genética , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Necroptose/genética
9.
Ecotoxicol Environ Saf ; 205: 111166, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32827966

RESUMO

N, N-Dimethylformamide (DMF) is a universal organic solvent which widely used in various industries, and a considerable amount of DMF is detected in industrial effluents. Accumulating animal and epidemiological studies have identified liver injury as an early toxic effect of DMF exposure; however, the detailed mechanisms remain poorly understood. In this study, we systematically integrated the quantitative proteomics, lipidomics, and metabolomics data obtained from the primary human hepatocytes exposed to DMF, to depict the complicated biochemical reactions correlated to liver damage. Eventually, we identified 284 deregulated proteins (221 downregulated and 63 upregulated) and 149 deregulated lipids or metabolites (99 downregulated and 50 upregulated) induced by DMF exposure. Further, the integration of the protein-metabolite (lipid) interactions revealed that N-glycan biosynthesis (involved in the endoplasmic reticulum stress and the unfolded protein response), bile acid metabolism (involved in the lipid metabolism and the inflammatory process), and mitochondrial dysfunction and glutathione depletion (both contributed to reactive oxygen species) were the typical biochemical reactions disturbed by DMF exposure. In summary, our study identified the versatile protein, lipid, and metabolite molecules in multiple signaling and metabolic pathways involved in DMF induced liver injury, and provided new insights to elucidate the toxic mechanisms of DMF.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Dimetilformamida/toxicidade , Poluentes Ambientais/toxicidade , Hepatócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Proteoma/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glutationa/metabolismo , Hepatócitos/metabolismo , Humanos , Lipidômica , Metabolômica , Cultura Primária de Células , Proteômica , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Testes de Toxicidade/métodos
10.
PLoS One ; 15(7): e0235745, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645073

RESUMO

Three-dimensional liver in vitro systems have recently attracted a lot of attention in drug development. These systems help to gain unprecedented insights into drug-induced liver injury (DILI), as they more closely reproduce liver biology, and as drug effects can be studied in isolated and controllable microenvironments. Many groups established human-based in vitro models but so far neglected the animal equivalent, although the availability of both models would be desirable. Animal in vitro models enable back- and forward translation of in vitro and in vivo findings, bridge the gap between rodent in vivo and human in vitro scenarios, and ultimately support the interpretation of data generated with preclinical species and humans. Since mice are often used in drug development and physiologically relevant in vitro systems are lacking, we established, for the first time, a mouse liver model that encompasses primary parenchymal and non-parenchymal cells with preserved viability and functionality over three weeks. Using our three-dimensional liver spheroids, we were able to predict the toxicity of known DILI compounds, demonstrated the interaction cascades between the different cell types and showed evidence of drug-induced steatosis and cholestasis. In summary, our mouse liver spheroids represent a valuable in vitro model that can be applied to study DILI findings, reported from mouse studies, and offers the potential to detect immune-mediated drug-induced liver toxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/imunologia , Modelos Biológicos , Cultura Primária de Células/métodos , Esferoides Celulares , Animais , Antibacterianos/toxicidade , Anti-Inflamatórios não Esteroides/toxicidade , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Hepatócitos/metabolismo , Imunidade Inata , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Esferoides Celulares/citologia , Esferoides Celulares/imunologia , Esferoides Celulares/metabolismo
11.
Toxicol Lett ; 333: 22-32, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32721574

RESUMO

HSCs (hepatic stellate cells) contribute to the excessive extracellular matrix (ECM) deposition, inflammatory pathways and crucial cell-cell interactions in hepatic disease leading to fibrosis. P2x7R is considered a potential orchestrater in liver fibrosis. For this reason, this work explored the role of P2x7R in liver fibrosis and the mechanism by which P2x7R in macrophages promotes fibrogenesis. In a model of liver fibrosis induced by administration of thioacetamide (TAA), inhibition of P2x7R with its selective inhibitor A438079 reversed TAA-induced liver damage and fibrosis. The mechanism was linked to inhibition of P2x7R-NLRP3 inflammasome activation and thereby infiltration of macrophages and neutrophils into the liver. This result indicated that the P2x7R-TLR4-NLRP3 axis is involved in the process of TGF-ß-mediated ECM deposition in HSCs. Ectopic overexpression of P2x7R lowered the threshold of extracellular matrix (ECM) deposition and maintained HSCs in an activated state. The culture medium of THP-1 macrophages stimulated by LPS/ATP aggravated ECM deposition in HSCs by activating P2x7R. Additionally, IL-1ß secreted by LPS / ATP activated macrophages amplified fibrosis. These data indicate that P2x7R plays a key regulative role in the activation and maintenance of HSCs promoted by macrophages. Thus, pharmacological inhibition of P2x7R could be a potential therapeutic mechanism to treat human liver fibrosis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Receptores Purinérgicos P2X7/metabolismo , Animais , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Retroalimentação Fisiológica , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Cirrose Hepática/patologia , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas do Receptor Purinérgico P2X/farmacologia , Piridinas/farmacologia , Tetrazóis/farmacologia , Tioacetamida/toxicidade
12.
Toxicol Lett ; 333: 49-61, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32726682

RESUMO

Hepatotoxicity induced by Mylabris has been reported in both clinical and animal experiments. Cantharidin (CTD), the main active compound of Mylabris was responsible for the hepatotoxicity, which aroused widespread concern. However, the mechanism of CTD hepatotoxicity remained unclear. In this study, LO2 cells were exposed to two doses of CTD (6.25 and 25 µM) for 12 h, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were measured. The metabolites in LO2 cells were profiled by LC-MS. Partial least squares discriminant analysis and orthogonal partial least squares discriminant analysis were used for screening potential biomarkers. The MetPA software was used for clustering and pathway analysis. Network pharmacology was used to predict the genes acted with potential biomarkers. Compared with the control group, the levels of ALT, AST, and LDH was significantly increased after CTD treatment. A total of 46 potential biomarkers for hepatotoxicity induced by CTD were identified. And downregulated potential biomarkers reflected the inhibitory effects of CTD toxicity on metabolism of LO2. Moreover, CTD-induced liver toxicity of LO2 cells is mainly related to three pathways: cysteine and methionine metabolism; glutathione metabolism; and glycine, serine, and threonine metabolism. Furtherly, the mRNA expression of CES2, DNMT1, NOS1, NOS3, S1PR2, and CES1 screened by network pharmacology were regulated by CTD. These studies provide valuable mechanistic insights into CTD-associated hepatotoxicity that will aid in the development of therapeutic prevention and treatment options for this liver disease.


Assuntos
Cantaridina/toxicidade , Doença Hepática Induzida por Substâncias e Drogas , Hepatócitos/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica/métodos , Estresse Oxidativo/efeitos dos fármacos , Biomarcadores/metabolismo , Técnicas de Cultura de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cromatografia Líquida/métodos , Relação Dose-Resposta a Droga , Hepatócitos/enzimologia , Hepatócitos/patologia , Humanos , Espectrometria de Massas/métodos , Metabolômica/instrumentação
13.
Ecotoxicol Environ Saf ; 203: 110899, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32678747

RESUMO

Liver is the earliest target for AFB1 toxicity in both human and animals. In the last decade, plant derived by-products have been used in animal feed to reduce AFB1 induced toxicity. In the present study we investigated whether the presence of 8% grape seed meal by-product is able to counteract the hepatotoxic effects produced by AFB1 in liver of pig after weaning exposed to the toxin through the contaminated feed for 28 days. Twenty four weaned cross-bred TOPIGS-40 piglets with an average body weight of 9.13±0.03 were allocated to the following experimentally treatments: control diet without AFB1 (normal compound feed for weaned pigs); contaminated diet with 320 mg kg-1 AFB1; GSM diet (compound feed plus 8% grape seed meal) and AFB1+GSM diet (320 mg kg-1 AFB1 contaminated feed plus 8% grape seed meal). Pigs fed AFB1 diet had altered performance, body weight decreasing with 25.1% (b.w.: 17.17 kg for AFB1 vs 22.92 kg for control). Exposure of piglets to AFB1 contaminated diet caused liver oxidative stress as well as liver histological damage, manly characterized by inflammatory infiltrate, fibrosis and parenchyma cells vacuolation when compared to control and GSM meal group. 94.12% of the total analysed genes (34) related to inflammation and immune response was up-regulated. The addition of GSM into the AFB1 diet diminished the gene overexpression and ameliorate histological liver injuries and oxidative stress. The protective effect of GSM diet in diminishing the AFB1 harmful effect was mediated through the decreasing of gene and protein expression of MAPKs and NF-κB signalling overexpressed by AFB1 diet. The inclusion of grape seed by-products in the diet of pigs after weaning might be used as a novel nutritional intervention to reduce aflatoxin toxicity.


Assuntos
Aflatoxina B1/toxicidade , Ração Animal/análise , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Fígado/efeitos dos fármacos , Sementes/química , Vitis/química , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Dieta , Fígado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Suínos , Desmame
14.
Chemosphere ; 257: 127177, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32480090

RESUMO

Zinc pyrithione (ZPT) is an extensively used microbicidal agent and its toxicity to multiple organs has been gradually recognized. However, details of the mechanism of ZPT toxicity are lacking and profile studies at metabolic level are still greatly limited. In this work we investigated the effects of ZPT on metabolic pathways of zebrafish liver after twenty-one days of exposure. Our integrated approach was underpinned by gas chromatography coupled with mass spectroscopy (GC-MS) and liver function analysis. Metabolomic profiles were generated from the livers of ZPT-treated zebrafish and 172 significantly altered metabolite peaks were detected. As a result, ZPT caused altered perturbation of metabolic pathways in male and female zebrafish liver. Moreover, ZPT induced the liver injury with the changes of the metabolites 2,4-diaminobutyric acid (2,4-DABA) with significant distinction between male and female zebrafish. ZPT caused gender-differentiated liver metabolic changes associated with the disruption of glycogenolysis and glycolysis metabolism, purine and pyrimidine metabolism, oxidative phosphorylation, arginine biosynthesis, and amino acid metabolism. Conclusively, exposure of ZPT may result in gender-differentiated metabolic abnormalities of adult zebrafish with induced hepatotoxicity.


Assuntos
Compostos Organometálicos/toxicidade , Piridinas/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/fisiologia , Animais , Diferenciação Celular , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Glicólise , Fígado/metabolismo , Masculino
15.
Am J Gastroenterol ; 115(8): 1153-1155, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32496340

Assuntos
Infecções por Coronavirus/fisiopatologia , Doenças do Sistema Digestório/fisiopatologia , Pneumonia Viral/fisiopatologia , Dor Abdominal/etiologia , Dor Abdominal/metabolismo , Dor Abdominal/fisiopatologia , Dor Abdominal/terapia , Assistência Ambulatorial , Anorexia/etiologia , Anorexia/metabolismo , Anorexia/fisiopatologia , Anorexia/terapia , Antibacterianos/efeitos adversos , Antipiréticos/efeitos adversos , Antivirais/efeitos adversos , Betacoronavirus , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Doença Hepática Induzida por Substâncias e Drogas/terapia , China , Infecções por Clostridium/diagnóstico , Infecções por Clostridium/tratamento farmacológico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/terapia , Diarreia/etiologia , Diarreia/metabolismo , Diarreia/fisiopatologia , Diarreia/terapia , Doenças do Sistema Digestório/etiologia , Doenças do Sistema Digestório/metabolismo , Doenças do Sistema Digestório/terapia , Endoscopia do Sistema Digestório , Gastroenterologia , Humanos , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Hepatopatias/terapia , Náusea/etiologia , Náusea/metabolismo , Náusea/fisiopatologia , Náusea/terapia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Pneumonia Viral/terapia , Probióticos/uso terapêutico , Sociedades Médicas , Vômito/etiologia , Vômito/metabolismo , Vômito/fisiopatologia
16.
Life Sci ; 254: 117770, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32407846

RESUMO

AIMS: Cadmium chloride has various industrial applications and considered an industrial and environmental pollutant. The aim of this study was to evaluate the effect of atorvastatin on Cadmium chloride-induced hepatotoxicity in male rats. MATERIALS AND METHODS: Fifty-six adult male rats, randomly were divided into 8 groups. Groups 1-3 were received atorvastatin (20 mg/kg) intragastrically for 15 days during which Cadmium chloride (1, 2, and 3 mg/kg) were given intraperitoneally from days 8 to 15. Groups 4-6 were as first three groups but animals were received vehicle of atorvastatin. Group 7 was received vehicle of atorvastatin and vehicle of Cadmium chloride and Group 8 was received atorvastatin and vehicle of Cadmium chloride according to timeline of other groups. On day 16, under full anesthesia, blood sampling was prepared from heart, and livers were dissected out to analyses the biochemical and histopathology studies. KEY FINDINGS: Cadmium chloride significantly increased aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) in the serum. Malondialdehyde (MDA) significantly increased and superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH) significantly decreased the in the liver following Cadmium chloride administration. Atorvastatin significantly improved the levels of MDA, SOD, GPx, GSH, but not ALT, AST, and ALP in Cadmium chloride-treated rats. In histopathological studies, atorvastatin could not improve injured liver tissues induced by Cadmium chloride. SIGNIFICANCE: Atorvastatin has beneficial effects in improving Cadmium chloride-induced antioxidative enzymes disturbance which may be contribute to improving liver function in male rats.


Assuntos
Atorvastatina/farmacologia , Alanina Transaminase/sangue , Fosfatase Alcalina/metabolismo , Animais , Antioxidantes/farmacologia , Aspartato Aminotransferases/sangue , Atorvastatina/metabolismo , Cádmio/toxicidade , Cloreto de Cádmio/efeitos adversos , Cloreto de Cádmio/farmacologia , Cloreto de Cádmio/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo
17.
Life Sci ; 254: 117760, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32418889

RESUMO

AIM: The present study focused on the possible underlying protective mechanisms of UDCA against GNT-induced hepatic injury. METHODS: For achieving this goal, adult male rats were allocated into 4 groups: normal control (received vehicle), GNT (100 mg/kg, i.p. for 8 days), UDCA (60 mg/kg, P.O. for 15 days), and GNT + UDCA (received UDCA for 15 days and GNT started from the 7th day and lasted for 8 days). RESULTS: The results revealed that UDCA significantly improved GNT-induced hepatic injury, oxidative stress, apoptosis, and inflammatory response. Interestingly, UDCA inhibited apoptosis by marked down-regulation of the Bax gene, Caspase-3, and cleaved Caspase-3 protein expressions while the level of Bcl-xL gene significantly increased. Moreover, UDCA strongly inhibited the inflammatory response through the down-regulation of both NF-κB-p65 and TNF-α accompanied by IL-10 elevation. Furthermore, the obtained results ended with the restored of mitochondria function that confirmed by electron microscopy. Histological analysis showed that UDCA remarkably ameliorated the histopathological changes induced by GNT. SIGNIFICANCE: UDCA may be a promising agent that can be used to prevent hepatotoxicity observed in GNT treatment. This effect could be attributed to, at least in part, the ability of UDCA to modulate NF-κB-p65/TNF-α, Bax/Bcl-xl/Caspase-3, and eNOS/iNOS signaling pathways.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Gentamicinas/antagonistas & inibidores , Gentamicinas/toxicidade , Hepatócitos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ácido Ursodesoxicólico/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Interações Medicamentosas , Hepatócitos/metabolismo , Hepatócitos/patologia , Masculino , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Wistar , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/metabolismo
18.
Chem Biol Interact ; 325: 109115, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32380060

RESUMO

UDP-glucuronosyltransferases (UGTs) are a family of phase II drug metabolizing enzymes that catalyze glucuronidation of numerous endogenous and exogenous substrates. Carbon tetrachloride (CCl4) is widely used to develop liver injuries mimicking human liver diseases. However, effects of CCl4 on the expression and activities of UGTs and the mechanism have not been fully elucidated. The present study aims to elucidate the dysregulation patterns of major UGTs induced by CCl4. Biochemical and histopathological results showed that CCl4 exerted hepatotoxicity in rats. The mRNA levels of UGTs were all significantly reduced in acute liver injury rats. However, mRNA levels of UGT1A1, 1A6, 2B1 and 2B2 were up-regulated while the UGT2B3, 2B6 and 2B12 levels were reduced in chronic CCl4-induced liver fibrosis rats. The protein expression of UGT1A1, 1A6 and 2B were decreased in acute liver injury rats. UGT1A1 and 1A6 proteins were increased, whereas UGT2B protein was reduced in liver fibrosis rats. In addition, CCl4 inhibited the enzyme activities of UGTs in rats. Moreover, the dysregulation of UGTs was accompanied by the decreased mRNA expression of Nrf2, CAR, FXR, PXR, PPAR-α and their corresponding target genes, except for Nrf2, HO-1, AhR and CYP1A1 in liver fibrosis rats. These findings suggest that dysregulation of UGTs under CCl4 exposure is isoform-specific, which could have a complex impact on drug efficacy and endogenous metabolism. Different exposure durations of CCl4 (single vs multiple doses) could have differential effects on rat hepatic UGTs expression.


Assuntos
Tetracloreto de Carbono/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Glucuronosiltransferase/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fibrose , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glucuronosiltransferase/genética , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição/metabolismo
19.
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
20.
Nat Cell Biol ; 22(6): 663-673, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32393887

RESUMO

The linear ubiquitin chain assembly complex (LUBAC), which consists of HOIP, SHARPIN and HOIL-1L, promotes NF-κB activation and protects against cell death by generating linear ubiquitin chains. LUBAC contains two RING-IBR-RING (RBR) ubiquitin ligases (E3), and the HOIP RBR is responsible for catalysing linear ubiquitination. We found that HOIL-1L RBR plays a crucial role in regulating LUBAC. HOIL-1L RBR conjugates monoubiquitin onto all LUBAC subunits, followed by HOIP-mediated conjugation of linear chains onto monoubiquitin, and these linear chains attenuate the functions of LUBAC. The introduction of E3-defective HOIL-1L mutants into cells augmented linear ubiquitination, which protected the cells against Salmonella infection and cured dermatitis caused by reduced LUBAC levels due to SHARPIN loss. Our results reveal a regulatory mode of E3 ligases in which the accessory E3 in LUBAC downregulates the main E3 by providing preferred substrates for autolinear ubiquitination. Thus, inhibition of HOIL-1L E3 represents a promising strategy for treating severe infections or immunodeficiency.


Assuntos
Proteínas de Transporte/fisiologia , Morte Celular , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Dermatite de Contato/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Salmonelose Animal/imunologia , Ubiquitina-Proteína Ligases/fisiologia , Ubiquitina/metabolismo , Animais , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Dermatite de Contato/metabolismo , Dermatite de Contato/patologia , Embrião de Mamíferos/imunologia , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Fibroblastos/imunologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/metabolismo , Salmonella/patogenicidade , Salmonelose Animal/metabolismo , Salmonelose Animal/patologia , Índice de Gravidade de Doença , Transdução de Sinais , Ubiquitinação
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