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1.
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
2.
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
3.
Toxicology ; 438: 152458, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32289347

RESUMO

Kynurenine (Kyn) plays an important role as an immune check-point molecule and regulates various immune responses through its aryl hydrocarbon receptor (Ahr). Kyn is synthesized by indoleamine 2,3-dioxygenase (Ido) and tryptophan 2,3-dioxygenase (Tdo). Ido contributes approximately 90% of tryptophan catabolism. Although Kyn is increased in various liver disorders, the roles of Kyn in liver injury are complicated because Ido1, Ido2, and Tdo are activated in different cell types. In this study, the roles of Ido2 in carbon tetrachloride (CCl4; 1 ml/kg, i.p.)-induced acute liver injury were examined using Ido2 knockout mice and Ido2 inhibitor. After CCl4 treatment, the ratio of Kyn to tryptophan and levels of Kyn in the liver were increased, accompanied by activation of Ahr-mediated signaling, as revealed by increased nuclear Ahr and Cyp1a1 mRNA. Knockout of Ido2 (Ido2-/-) and treatment with Ido2 inhibitor 1-methyl-D-tryptophan (D-1MT; 100 mg/kg, i.p.) attenuated CCl4-induced liver injury, with decreased induction of Ahr-mediated signaling. Administration of D-Kyn (100 mg/kg, i.p.) to Ido2-/- mice canceled the effect of Ido2 deficiency and exacerbated acute liver damage by CCl4 treatment. In addition, liver fibrosis induced by repeated CCl4 administration was suppressed in Ido2-/- mice. In conclusion, the action of Ido2 and Kyn in the liver may prevent severe hepatocellular damage and liver fibrosis.


Assuntos
Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Cirrose Hepática Experimental/enzimologia , Fígado/enzimologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Progressão da Doença , Inibidores Enzimáticos/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Hepatócitos/patologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/deficiência , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais
4.
Yi Chuan ; 42(4): 374-379, 2020 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-32312706

RESUMO

To systematically study the susceptible genetic markers for liver injury induced by anti-tuberculosis drugs in the Chinese population, 109 genes related to drug metabolism, transport and immunity were captured by Haloplex capture technique from DNA samples of 41 patients with liver injury induced by anti-tuberculosis drugs and 39 healthy controls, and sequenced completely. Association study was conducted using Plink software. To verify the significant candidate SNPs, the χ 2 study was expanded to the control group from the 1000-person Genome Project of the East Asian population. SIFT and Polyphen2 software were used to predict the functional significance of the associated SNPs. Our results identified the UGT1A4 rs2011404 (χ 2 = 4.6809, P = 0.0305) as a susceptible genetic marker for liver injury induced by anti-tuberculosis drugs, and rs2011404 mutation might contribute to UGT1A4 protein dysfunction. This study has provided a potentially useful reference for establishing the precision medicine in rational uses of anti-tuberculosis drugs in the clinic.


Assuntos
Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/genética , Marcadores Genéticos , Predisposição Genética para Doença , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , China , Glucuronosiltransferase/genética , Humanos , Polimorfismo de Nucleotídeo Único , Tuberculose/tratamento farmacológico
5.
Nat Commun ; 11(1): 1939, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32321925

RESUMO

Acetaminophen (APAP) is the main cause of acute liver failure in the West. Specific efficacious therapies for acute liver failure (ALF) are limited and time-dependent. The mechanisms that drive irreversible acute liver failure remain poorly characterized. Here we report that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage after toxic liver injury. Our data demonstrate that blocking platelet CLEC-2 signalling enhances liver recovery from acute toxic liver injuries (APAP and carbon tetrachloride) by increasing tumour necrosis factor-α (TNF-α) production which then enhances reparative hepatic neutrophil recruitment. We provide data from humans and mice demonstrating that platelet CLEC-2 influences the hepatic sterile inflammatory response and that this can be manipulated for therapeutic benefit in acute liver injury. Since CLEC-2 mediated platelet activation is independent of major haemostatic pathways, blocking this pathway represents a coagulopathy-sparing, specific and novel therapy in acute liver failure.


Assuntos
Acetaminofen/efeitos adversos , Plaquetas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Lectinas Tipo C/imunologia , Neutrófilos/imunologia , Animais , Tetracloreto de Carbono/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Humanos , Lectinas Tipo C/genética , Fígado/efeitos dos fármacos , Fígado/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
6.
Life Sci ; 248: 117475, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32119963

RESUMO

AIMS: Liver fibrosis is a crucial pathological feature which could result in cirrhosis and hepatocarcinoma. But until now, there is no favourable treatment for it. Apigenin (APG) is a flavonoid, which exhibits efficient anti-liver fibrosis activity, but its underlying mechanisms were rarely studied. So this work aims to estimate the potential therapeutic action of APG on liver fibrosis rats and to gain insight into its system-level mechanisms. MAIN METHODS: Hepatic fibrosis was induced by CCl4 in Wistar rats, and APG was given in the light of the regimen. Biochemical indexes, histopathological change and immunohistochemistry of liver were evaluated. The optimal effect group of APG was selected for further transcriptomic and proteomic analysis. KEY FINDINGS: APG ameliorated liver fibrosis via reducing the levels of AST, ALT, ALP, LDH, Hyp, TP, TB, DB, HA, LN, PCIII and IV-C, mitigating fibrosis and inflammation of liver in H&E and Masson staining. Mechanistically, APG elevated the activity of ALB, SOD and GSH-PX with reducing the level of MDA. The results of microarray and TMT revealed that 4919 genes and 4876 proteins were differentially expressed in the APG and model groups. Besides, transcriptomics and proteomics analyses unfolded 120 overlapped proteins, enriched in 111 GO terms containing apoptotic process, angiogenesis, cell migration and proliferation, etc. Meanwhile, KEGG pathway analysis showed that 26 pathways containing HIF-1/MAPK/eNOS/VEGF/PI3K/Akt signaling pathway, regulation of actin cytoskeleton and focal adhesion mostly. SIGNIFICANCE: APG can ameliorate CCl4-induced liver fibrosis via VEGF-mediated FAK phosphorylation through the MAPKs, PI3K/Akt, HIF-1, ROS, and eNOS pathways, which may hopefully become the anti-liver fibrosis activity of natural product.


Assuntos
Anti-Inflamatórios/farmacologia , Apigenina/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Alanina Transaminase/genética , Alanina Transaminase/metabolismo , Albuminas/metabolismo , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Bilirrubina/sangue , Tetracloreto de Carbono/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/patologia , Masculino , Malondialdeído/antagonistas & inibidores , Malondialdeído/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Proteômica/métodos , Ratos , Ratos Wistar , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Toxicol Appl Pharmacol ; 391: 114915, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32035082

RESUMO

Idiosyncratic drug-induced liver injury (IDILI) is a severe disease that cannot be detected during drug development. It has been shown that hepatotoxicity of some compounds associated with IDILI becomes apparent when these are combined in vivo and in vitro with LPS or TNF. Among these compounds trovafloxacin (TVX) induced apoptosis in the liver and increased pro-inflammatory cytokines in mice exposed to LPS/TNF. The hepatocyte survival and the cytokine release after TNF/LPS stimulation relies on a pulsatile activation of NF-κB. We set out to evaluate the dynamic activation of NF-κB in response to TVX + TNF or LPS models, both in mouse and human cells. Remarkably, TVX prolonged the first translocation of NF-κB induced by TNF both in vivo and in vitro. The prolonged p65 translocation caused by TVX was associated with an increased phosphorylation of IKK and MAPKs and accumulation of inhibitors of NF-κB such as IκBα and A20 in HepG2. Coherently, TVX suppressed further TNF-induced NF-κB translocations in HepG2 leading to decreased transcription of ICAM-1 and inhibitors of apoptosis. TVX prolonged LPS-induced NF-κB translocation in RAW264.7 macrophages increasing the secretion of TNF. In summary, this study presents new, relevant insights into the mechanism of TVX-induced liver injury underlining the resemblance between mouse and human models. In this study we convincingly show that regularly used toxicity models provide a coherent view of relevant pathways for IDILI. We propose that assessment of the kinetics of activation of NF-κB and MAPKs is an appropriate tool for the identification of hepatotoxic compounds during drug development.


Assuntos
Antibacterianos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fluoroquinolonas/toxicidade , Lipopolissacarídeos/farmacologia , Naftiridinas/toxicidade , Fator de Transcrição RelA/efeitos dos fármacos , Fator de Transcrição RelA/genética , Translocação Genética/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Animais , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/genética , Citocinas/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismo
8.
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
9.
Cell Death Dis ; 11(1): 70, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31988281

RESUMO

Previous studies have shown that tumor necrosis factor (TNF)-α is a mediator of hepatotoxicity in liver injury. Moreover, TNF-α has also been reported to have a protective effect in liver regeneration, yet the function of TNF-α during liver injury remains controversial. Here, we report that the concentration of TNF-α determines its functions. High concentrations of TNF-α could aggravate LPS-induced liver injury. However, the TNF-α level was unchanged during APAP-induced liver injury, which exerted a protective effect. We expected that the concentration of TNF-α may affect its function. To test this hypothesis, TNF-α-/- rats or hepatocyte cells were treated with different concentrations of TNF-α. We found low TNF-α could reduce the levels of ALT and AST in the plasma of TNF-α-/- rats and promote the proliferation of hepatocyte cells. However, the levels of ALT and AST increased gradually with increasing TNF-α concentration after reaching the lowest value. Moreover, we showed that TNF-α affects the cell proliferation and cell death of hepatocytes by regulating Yap activity. Low TNF-α promoted Yap1 nuclear translocation, triggering the proliferation of hepatocytes. However, high TNF-α triggered the phosphorylation and inactivation of Yap1, preventing its nuclear import and consequently promoting cell death. Collectively, our findings provide novel evidence that the concentration of TNF-α is an important factor affecting its function in liver injury, which may provide a reference for the clinical treatment of liver injury.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Hepatócitos/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Acetaminofen/toxicidade , Alanina Transaminase/sangue , Animais , Animais Geneticamente Modificados , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/genética , Aspartato Aminotransferases/sangue , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Hepatócitos/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Fosforilação , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
10.
Am J Physiol Gastrointest Liver Physiol ; 318(3): G504-G517, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31928221

RESUMO

Activation of hepatic stellate cells (HSCs), characterized by development of a robust actin cytoskeleton and expression of abundant extracellular matrix (ECM) proteins, such as type 1 collagen (COL.1), is a central cellular and molecular event in liver fibrosis. It has been demonstrated that HSCs express both myocardin and myocardin-related transcription factor-A (MRTF-A). However, the biological effects of myocardin and MRTF-A on HSC activation and liver fibrosis, as well as the molecular mechanism under the process, remain unclear. Here, we report that myocardin and MRTF-A's expression and nuclear accumulation are prominently increased during the HSC activation process, accompanied by robust activation of actin cytoskeleton dynamics. Targeting myocardin and MRTF-A binding and function with a novel small molecule, CCG-203971, led to dose-dependent inhibition of HSC actin cytoskeleton dynamics and abrogated multiple functional features of HSC activation (i.e., HSC contraction, migration and proliferation) and decreased COL.1 expression in vitro and liver fibrosis in vivo. Mechanistically, blocking the myocardin and MRTF-A nuclear translocation pathway with CCG-203971 directly inhibited myocardin/MRTF-A-mediated serum response factor (SRF), and Smad2/3 activation in the COL.1α2 promoter and indirectly abrogated actin cytoskeleton-dependent regulation of Smad2/3 and Erk1/2 phosphorylation and their nuclear accumulation. Finally, there was no effect of CCG-203971 on markers of inflammation, suggesting a direct effect of the compound on HSCs and liver fibrosis. These data reveal that myocardin and MRTF-A are two important cotranscriptional factors in HSCs and represent entirely novel therapeutic pathways that might be targeted to treat liver fibrosis.NEW & NOTEWORTHY Myocardin and myocardin-related transcription factor-A (MRTF-A) are upregulated in activated hepatic stellate cells (HSCs) in vitro and in vivo, closely associated with robustly increased actin cytoskeleton remodeling. Targeting myocardin and MRTF-A by CCG-203971 leads to actin cytoskeleton-dependent inhibition of HSC activation, reduced cell contractility, impeded cell migration and proliferation, and decreased COL.1 expression in vitro and in vivo. Dual expression of myocardin and MRTF-A in HSCs may represent novel therapeutic targets in liver fibrosis.


Assuntos
Citoesqueleto de Actina/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Células Estreladas do Fígado/metabolismo , Cirrose Hepática Experimental/metabolismo , Fígado/metabolismo , Proteínas Nucleares/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/patologia , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/patologia , Cirrose Hepática Experimental/prevenção & controle , Masculino , Camundongos Endogâmicos BALB C , Ácidos Nipecóticos/farmacologia , Proteínas Nucleares/genética , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais , Proteínas Smad Reguladas por Receptor/metabolismo , Fatores de Tempo , Transativadores/genética , Fatores de Transcrição/genética , Regulação para Cima
11.
Oxid Med Cell Longev ; 2020: 7504521, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998441

RESUMO

Serotonin is involved in the pathological processes of several liver diseases via the regulation of inflammatory response and oxidative stress. We aimed to investigate the role of serotonin in Concanavalin A- (Con A-) induced acute liver injury (ALI). ALI was induced in C57B/6 wild-type (WT) mice and tryptophan hydroxylase 1 (TPH1) knockout mice through tail vein injection of Con A (15 mg/kg body weight). Another group of TPH1 knockout ALI mice was supplied with 5-hydroxytryptophan (5-HTP) in advance to recover serotonin. The blood and liver tissues of mice were collected in all groups. Markedly increased serum levels of serotonin were identified after the injection of Con A. Increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and stronger hepatic tissue pathology were detected, suggesting that serotonin could mediate Con A-induced liver damage. Serotonin significantly facilitated the release of serum and intrahepatic inflammatory cytokines, including interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-17A (IL-17A), interferon-gamma (IFN-γ), and tumor necrosis-alpha (TNF-α), after the administration of Con A. In addition, serotonin significantly increased the intrahepatic levels of oxidative stress markers malonaldehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) and decreased antioxidant stress indicator glutathione (GSH) in Con A-treated mice. Additionally, serotonin promoted hepatocyte apoptosis and autophagy based on B-cell lymphoma-2 (Bcl-2), Bcl-2-asociated X protein (Bax), and Beclin-1 levels and TUNEL staining. More importantly, serotonin activated nuclear factor kappa B (NF-κB) and upregulated the hepatic expressions of high mobility group protein B1 (HMGB1), toll-like receptor-4 (TLR4), and downstream molecules in Con A-mediated liver injury. Serotonin 2A receptor was upregulated in liver tissue after Con A injection, and serotonin 2A receptor antagonist Ketanserin protected against Con A-induced hepatitis. These results indicated that serotonin has the potential to aggravate Con A-induced ALI via the promotion of inflammatory response, oxidative stress injury, and hepatocyte apoptosis and the activation of hepatic HMGB1-TLR signaling pathway and serotonin 2A receptor.


Assuntos
Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/sangue , Concanavalina A/efeitos adversos , Serotonina/sangue , Transdução de Sinais/efeitos dos fármacos , Animais , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Concanavalina A/farmacologia , Citocinas/sangue , Citocinas/genética , Masculino , Malondialdeído/sangue , Camundongos , Camundongos Knockout , Óxido Nítrico/sangue , Óxido Nítrico/genética , Peroxidase/sangue , Peroxidase/genética , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/genética , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo
12.
DNA Cell Biol ; 39(3): 349-354, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31905014

RESUMO

The liver is susceptible to drug toxicity due to its vital role in xenobiotic metabolism and elimination. In addition to human leukocyte antigen (HLA) variants, which were previously determined as risk factors for drug-induced liver injury (DILI) due to co-amoxiclav, other non-HLA genes may contribute to hepatotoxicity risk. In this study, the association between DILI due to co-amoxiclav and several non-HLA genes was investigated. Association of variants in candidate genes (SOD2, GPX1, GSTM1, and GSTT1) with DILI due to various drugs was reported previously in other DILI cohorts. This study examined relevance in a co-amoxiclav-DILI cohort. One hundred sixty-five co-amoxiclav DILI cases were recruited from several European countries by two different studies (DILIGEN and iDILIC). A North-East England population group (n = 334) was used as the control group. PCR assays were used to genotype for the GSTM1 and GSTT1 null alleles with TaqMan SNP genotyping assays used for SOD2 (rs4880) and GPX1 (rs1050450). Fisher's exact test was used to assess differences in significance between cases and controls. None of the studied variants (SOD2 rs4880, GPX1 rs1050450, GSTM1 null allele, and GSTT1 null allele) was significantly associated with co-amoxiclav DILI compared with the control group. No significant differences between cases and controls were seen when combined SOD2/GPX1 genotypes and GST genotypes were considered. Despite the possible functional relevance and the previously reported contribution of the selected genes to DILI, our study failed to confirm associations between the selected genes and liver injury induced by co-amoxiclav.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/genética , Estresse Oxidativo , Polimorfismo de Nucleotídeo Único , Idoso , Combinação Amoxicilina e Clavulanato de Potássio/toxicidade , Antibacterianos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Feminino , Glutationa Peroxidase/genética , Glutationa Transferase/genética , Humanos , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Superóxido Dismutase/genética
13.
Toxicol Lett ; 320: 1-8, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31756458

RESUMO

With the spread of hexavalent chromium [Cr(VI)] contamination, risk of exposure in non-occupational populations is increasing. The liver is the main target organ for Cr(VI) accumulation; however, the effect of long-term Cr(VI) exposure on liver toxicity is largely unknown. In this study, we investigated the effect of chronic Cr(VI) exposure on liver fibrosis and its possible mechanism. Mice were injected with Cr(VI) for two months, and our results showed Cr(VI) treatment caused liver toxicity characterized by liver structure disorganization, liver dysfunction, and antioxidant enzyme system inhibition. The development of liver fibrosis was also found via the emergence of collagen fibril deposition, increased expression of extracellular matrix-related genes, activation of hepatic stellate cells (HSCs) and increase the expression levels of Hedgehog (Hh) signaling pathway-related molecules. To demonstrate the role of Hh signaling in the regulation of Cr(VI)-induced liver fibrosis, genetically modified mice with heterozygous deficiency of Shh (Shh+/-) were used. In the Shh+/- mice, Hh signaling, HSCs activation and liver fibrosis development were all ameliorated. In conclusion, we demonstrated that Cr(VI)-induced liver fibrosis development resulted from Hh pathway-mediated HSCs activation. Our findings strongly suggest that inhibition of Hh pathway may help in the development of new strategies for Cr(VI)-associated liver fibrosis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Cromo , Proteínas Hedgehog/metabolismo , Células Estreladas do Fígado/metabolismo , Cirrose Hepática Experimental/metabolismo , Fígado/metabolismo , Dicromato de Potássio , Transdução de Sinais , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Proteínas Hedgehog/deficiência , Proteínas Hedgehog/genética , Células Estreladas do Fígado/patologia , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout
14.
Toxicol Lett ; 321: 12-20, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31830553

RESUMO

Liver injury is one of the main toxic effect of sulfasalazine (SASP). However, the toxicological mechanism of SASP-induced liver injury remains unclear. In the present study, the liver injury was induced by orally treatment with SASP for 4 weeks in mice. The hepatic mRNA profiles were detected by RNA sequencing and the differentially expressed genes (DEGs) were analyzed by bioinformatics methods. The elevated serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TBIL), combined with the hepatic histopathological features verified that liver injury was successfully caused by SASP. Transcriptomic results showed that 187 genes (fold change > 1.5 and P < 0.05) were differentially expressed, of which 106 genes were up-regulated and 81 genes were down-regulated in SASP-treated group. Moreover, the further analysis showed that these 187 differentially expressed genes (DEGs) were enriched in 123 GO terms, which mainly including oxidation-reduction process, oxidoreductase activity and epoxygenase P450 pathway. KEGG pathway analysis showed 30 pathways including chemical carcinogenesis, retinol metabolism, arachidonic acid metabolism, linoleic acid metabolism and glutathione metabolism. Among these 187 DEGs, the top 22 hub genes were screened from network of protein-protein interaction (PPI) and verified by qRT-PCR. The results showed that the mRNA levels of hepatic drug-metabolizing enzymes, including cyp2b50, cyp2c50, cyp2c39, cyp2c38, cyp2c29, cyp2c54, cyp2c55, cyp2a5, gsta1, gsta2, gstt2, gstm2 and ephx1, were significantly up-regulated, while egfr and egr1 were down-regulated in SASP-treated group. Moreover, the mRNA levels of egfr and cyp2c55 exhibited a dose-dependent changes in SASP groups. Western blotting verified that the changes of protein levels of EGFR and CYP2C55 were consistent with mRNA levels. Considering that egfr has the highest score in PPI degree and cyp2c55 has the largest fold change in qPCR analysis, our present results suggested that the toxicological mechanisms of SASP-induced liver injury might be related to multi-biological processes and pathways, and egfr and cyp2c55 may play important roles in SASP-induced liver injury. The present study would be helpful for better understanding the hepatotoxic mechanism of SASP. However, the precise mechanism still needs further research.


Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/genética , Perfilação da Expressão Gênica , Fígado/efeitos dos fármacos , Sulfassalazina/toxicidade , Transcriptoma/efeitos dos fármacos , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos ICR , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de Tempo
15.
Int J Infect Dis ; 91: 223-231, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31838216

RESUMO

OBJECTIVES: The aim of this study was to identify the relationship between B-cell CLL/lymphoma 2 (BCL2) polymorphisms and susceptibility to anti-tuberculous therapy-associated drug-induced liver injury (ATT-DILI). METHODS: A total of 746 tuberculosis (TB) patients were enrolled in this study. Twenty-one selected single nucleotide polymorphisms in BCL2 were analyzed by custom-by-design 2×48-Plex SNPscan kit. The allele and genotype frequencies between patients with and without ATT-DILI were compared using three different genetic models. RESULTS: A total of 727/746 participants were successfully genotyped, and 112 of them were diagnosed with ATT-DILI. The A allele of rs8085707, G allele of rs76986960, and A allele of rs949037 conferred an increased risk of ATT-DILI, with estimated odd ratios (ORs) of 2.181 (95% confidence interval (CI) 1.345-3.536, p=0.001), 1.983 (95% CI 1.060-3.709, p=0.029), and 1.390 (95% CI 1.032-1.873, p=0.03), respectively. Bonferroni correction indicated that the A allele of rs8085707 was a risk factor for ATT-DILI (Bonferroni correction: p=0.026). The additive model suggested that patients with the AA genotype of rs8085707 had a significantly higher risk of ATT-DILI compared with those with the GG genotype (Bonferroni correction: p=0.036). The influence of BCL2 polymorphisms on clinical characteristics (clinical symptoms, disease subtypes, and laboratory indicators) was also identified. CONCLUSIONS: This study is novel in suggesting an association between BCL2 polymorphisms and the risk of ATT-DILI.


Assuntos
Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-bcl-2/genética , Tuberculose/tratamento farmacológico , Adulto , Alelos , Antituberculosos/uso terapêutico , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Doença Hepática Induzida por Substâncias e Drogas/etnologia , Doença Hepática Induzida por Substâncias e Drogas/genética , China/etnologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Tuberculose/complicações , Tuberculose/etnologia , Adulto Jovem
16.
Xenobiotica ; 50(6): 654-662, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31631733

RESUMO

1. The expression and activity of drug-metabolizing enzymes are known to affect the pharmacokinetics of drugs metabolized in the liver. Here, we assessed the effect of acetaminophen (APAP)-induced hepatotoxicity on the mRNA expression of drug-metabolizing enzymes and elucidated the underlying mechanism using three-dimensional (3D) cultures of HepG2 cells.2. 3D culture cells enabled us to establish an in vitro model of APAP-induced hepatotoxicity which showed the increase in N-acetyl-p-benzoquinone imine production, reactive oxygen species (ROS) generation and cellular injury.3. In this 3D culture model, APAP treatment significantly increased the mRNA expression of drug-metabolizing enzymes (cytochrome P450 [CYP]3A4, CYP2E1 and UDP-glucuronosyltransferase 1A6) and their nuclear receptors (pregnane X receptor and constitutive androstane receptor) compared with untreated cells. Treatment with N-acetylcysteine, a therapeutic agent for APAP-induced hepatotoxicity, suppressed these increases. In addition, the mRNA expression of drug-metabolizing enzymes and nuclear receptors were elevated depending on the concentration of H2O2, one of ROS involved in the development of APAP-induced hepatotoxicity. The mRNA expression of nuclear receptors increased before that of drug-metabolizing enzymes.4. In conclusion, ROS may induce the mRNA expression of nuclear receptors and promote the transcription of drug-metabolizing enzymes in the in vitro model of APAP-induced hepatotoxicity.


Assuntos
Acetaminofen/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , RNA Mensageiro/metabolismo , Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/genética , Citocromo P-450 CYP2E1/metabolismo , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Inativação Metabólica , Fígado , Taxa de Depuração Metabólica , Receptores Citoplasmáticos e Nucleares
17.
Int J Clin Pharmacol Ther ; 58(2): 67-73, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31670652

RESUMO

OBJECTIVE: Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is a major adverse reaction of tuberculosis (TB) therapy. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master transcription factor encoded by the NFE2L2 gene. Nrf2 regulates the expression of antioxidant genes which affect the kinetics of drugs and other xenobiotics, and plays a key role in the regulation of cellular redox status. We investigated the potential association of NFE2L2 single-nucleotide polymorphisms (SNPs) with ATDH. MATERIALS AND METHODS: 280 newly diagnosed TB patients were recruited in this prospective study and were followed up for 3 months after initiating anti-TB therapy. Five tagSNPs (rs2001350, rs6726395, rs1962142, rs13001694, and rs2364723) were selected based on a Han Chinese panel in the International HapMap database with a minor allele frequency < 5% and an r2 threshold of 0.8. RESULTS: Of the 280 subjects recruited in this research, there were 24 patients diagnosed with ATDH, 223 subjects without ATDH, and 33 individuals excluded during the follow-up. After adjusting for confounding factors including sex, age, smoking status, and body mass index, there was no statistically significant difference. CONCLUSION: Our results suggest that NFE2L2 variants may not contribute to the pathogenesis of ATDH in a Chinese population. Further large sample studies and various population studies are needed to fully explore the association between ATDH and NFE2L2 polymorphism.


Assuntos
Antioxidantes/metabolismo , Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/genética , Fator 2 Relacionado a NF-E2/genética , Antituberculosos/farmacocinética , Grupo com Ancestrais do Continente Asiático , China , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Tuberculose/tratamento farmacológico
18.
Toxicol Appl Pharmacol ; 388: 114869, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31863799

RESUMO

Ammonia (NH3), a toxic gas, is an important cause of atmospheric haze and one of the main pollutants in air environment of poultry houses, threatening the health of human beings and poultry. However, little is known about the effect of NH3 on liver apoptotic damage. This study aimed to investigate the mechanism of oxidative stress-mediated apoptosis caused by NH3 in chicken livers and whether miR-187-5p/apaf-1 axis was involved in this mechanism. Here we duplicated NH3 poisoning model of chickens for fattening to study the ultrastructure of chicken livers, apoptosis rate, oxidative stress indexes, miR-187-5p, and apoptosis-related genes. Obvious apoptotic characteristics of liver tissues exposed to excess NH3 were observed, and the apoptosis rate increased. Excess NH3 decreased the activities of catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-Px), and increased the content of malondialdehyde (MDA), suggesting that oxidative stress occurred. miR-187-5p decreased, and apoptotic protease activating factor-1 (apaf-1) increased, indicating that excess NH3 dysregulated miR-187-5p/apaf-1 axis. The expression of tumor protein p53 (p53), Bcl-2 associated X protein (Bax), Bcl-2 homologous antagonist/killer (Bak), Cytochrome-c (Cyt-c), Caspase-9, Caspase-8, and Caspase-3 was promoted, and the expression of B-cell lymphoma-2 (Bcl-2) was inhibited, resulting in apoptosis. Moreover, oxidative stress indexes, miR-187-5p, and apoptosis-related genes changed in dose- and time-dependent manner. Altogether, miR-187-5p/apaf-1 axis participated in oxidative stress-mediated apoptosis caused by NH3 via mitochondrial pathway in the livers of chickens for fattening. This study may provide new ideas to study the mechanism of liver apoptotic damage induced by NH3 exposure.


Assuntos
Amônia/envenenamento , Fator Apoptótico 1 Ativador de Proteases/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , MicroRNAs/metabolismo , Mitocôndrias/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Galinhas , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Mitocôndrias/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Regulação para Cima/efeitos dos fármacos
19.
Food Chem Toxicol ; 136: 111075, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31877367

RESUMO

Alcohol-related liver disease (ALD) and drug-induced liver injury (DILI) are common causes of severe liver disease, and successful treatments are lacking. Autophagy plays a protective role in both ALD and DILI by selectively removing damaged mitochondria (mitophagy), lipid droplets (lipophagy), protein aggregates and adducts in hepatocytes. Autophagy also protects against ALD by degrading interferon regulatory factor 1 (IRF1) and damaged mitochondria in hepatic macrophages. Specifically, we will discuss selective autophagy for removal of damaged mitochondria and lipid droplets in hepatocytes and autophagy-mediated degradation of IRF1 in hepatic macrophages as protective mechanisms against alcohol-induced liver injury and steatosis. In addition, selective autophagy for removal of damaged mitochondria and protein adducts for protection against DILI is discussed in this review. Development of new therapeutics for ALD and DILI is greatly needed, and selective autophagy pathways may provide promising targets. Drug and alcohol effects on autophagy regulation as well as protective mechanisms of autophagy against DILI and ALD are highlighted in this review.


Assuntos
Autofagia , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Etanol/efeitos adversos , Hepatopatias Alcoólicas/fisiopatologia , Animais , Autofagia/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Humanos , Fator Regulador 1 de Interferon/genética , Fator Regulador 1 de Interferon/metabolismo , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/metabolismo
20.
J Infect Chemother ; 26(1): 63-68, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31405785

RESUMO

Antituberculosis drug-induced adverse drug reactions (ADRs) has been attached the increasing attention currently. And many host genetic determinants of ADRs have been identified. However, the possible relationship between long non-coding RNA (lncRNA) and ADRs is little investigated in tuberculosis (TB). We conducted a prospective survey and comprehensively collected the information of diverse ADRs during antituberculosis therapy. Next, we analyzed whether single nucleotide polymorphisms (SNPs) within lncRNA AC079767.4 gene are associated with ADRs development of patients with TB. Our results showed that the overall occurrence rate of ADRs due to TB treatment was 16.39% (70/427), of which the anti-tuberculosis drug-induced hepatotoxicity (ATDH) constituted the most common adverse events with prevalence rate of 12.88% (55/427). Notably, TB patients carrying T allele-containing genotypes in rs1055229 locus potentially presented a greater risk (1.85-fold, 95%CI = 1.04-3.28) for developing ATDH when compared with those CC genotype carriers, 17.28% versus. 10.19%, respectively, with the age- and gender -adjusted p-value of 0.035. Our data suggest that the ADRs exhibit serious morbidity in TB patients in West China, and for the first time we show that the AC079767.4 rs1055229 is a potential genetic risk component for ATDH development. Further studies on larger population and other ethnic groups are needed to confirm our results.


Assuntos
Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , RNA Longo não Codificante/genética , Tuberculose/tratamento farmacológico , Adulto , Antituberculosos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
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