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1.
Toxicol Lett ; 350: 40-51, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34229068

RESUMO

In recent years, network-based methods have become an attractive analytical approach for toxicogenomics studies. They can capture not only the global changes of regulatory gene networks but also the relationships between their components. Among them, a causal reasoning approach depicts the mechanisms of regulation that connect upstream regulators in signaling networks to their downstream gene targets. In this work, we applied CARNIVAL, a causal network contextualisation tool, to infer upstream signaling networks deregulated in drug-induced liver injury (DILI) from gene expression microarray data from the TG-GATEs database. We focussed on six compounds that induce observable histopathologies linked to DILI from repeated dosing experiments in rats. We compared responses in vitro and in vivo to identify potential cross-platform concordances in rats as well as network preservations between rat and human. Our results showed similarities of enriched pathways and network motifs between compounds. These pathways and motifs induced the same pathology in rats but not in humans. In particular, the causal interactions "LCK activates SOCS3, which in turn inhibits TFDP1" was commonly identified as a regulatory path among the fibrosis-inducing compounds. This potential pathology-inducing regulation illustrates the value of our approach to generate hypotheses that can be further validated experimentally.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Toxicogenética , Animais , Humanos , Modelos Animais , Ratos
2.
Biomolecules ; 11(7)2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202146

RESUMO

Liver malignant tumors (LMTs) represent a serious adverse drug event associated with drug-induced liver injury. Increases in endocrine-disrupting chemicals (EDCs) have attracted attention in recent years, due to their liver function-inhibiting abilities. Exposure to EDCs can induce nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, which are major etiologies of LMTs, through interaction with nuclear receptors (NR) and stress response pathways (SRs). Therefore, exposure to potential EDC drugs could be associated with drug-induced LMTs. However, the drug classes associated with LMTs and the molecular initiating events (MIEs) that are specific to these drugs are not well understood. In this study, using the Food and Drug Administration Adverse Event Reporting System, we detected LMT-inducing drug signals based on adjusted odds ratios. Furthermore, based on the hypothesis that drug-induced LMTs are triggered by NR and SR modulation of potential EDCs, we used the quantitative structure-activity relationship platform for toxicity prediction to identify potential MIEs that are specific to LMT-inducing drug classes. Events related to cell proliferation and apoptosis, DNA damage, and lipid accumulation were identified as potential MIEs, and their relevance to LMTs was supported by the literature. The findings of this study may contribute to drug development and research, as well as regulatory decision making.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Bases de Dados Factuais/estatística & dados numéricos , Neoplasias Hepáticas/epidemiologia , United States Food and Drug Administration/estatística & dados numéricos , Carbamatos/efeitos adversos , Carbamatos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/genética , Previsões , Humanos , Imidazóis/efeitos adversos , Imidazóis/toxicidade , Isoquinolinas/efeitos adversos , Isoquinolinas/toxicidade , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/toxicidade , Pirrolidinas/efeitos adversos , Pirrolidinas/toxicidade , Receptores de Calcitriol/genética , Receptores de Estrogênio/genética , Sulfonamidas/efeitos adversos , Sulfonamidas/toxicidade , Estados Unidos/epidemiologia , Valina/efeitos adversos , Valina/análogos & derivados , Valina/toxicidade
3.
Free Radic Biol Med ; 174: 57-65, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34324981

RESUMO

Many studies have investigated the role of receptor-interacting protein 1 (RIP1) kinase in acetaminophen (APAP) overdose-induced acute liver injury. However, the results were not consistent and there still remain controversies. Importantly, in these previous studies, the usage of DMSO to dissolve the RIP1 kinase inhibitor Nec-1, resulted in misleading conclusion. Our study aimed to determine the role of RIP1 kinase in APAP-induced liver injury, via genetically or pharmaceutically inhibition of RIP1 kinase activity. Our results indicated that APAP-induced liver injury was significantly attenuated in RIP1 kinase-dead (Rip1K45A/K45A) mice compared to WT control. High dosage of APAP-induced mortality was also rescued by RIP1 kinase inactivation. In agreement, RIP1 kinase inhibitor, Nec-1 which was formulated with PEG400, could efficiently alleviate APAP-induced hepatotoxicity. For the underlying mechanism, our results suggested that RIP1 kinase inactivation did not influence the hepatic GSH depletion, but significantly reduced the hepatic cell death and inflammation induced by APAP treatment. Using bone marrow transplantation model, we also demonstrated that it was RIP1 kinase activity in tissue-resident hepatic cells other than hematopoietic-derived cells mainly responsible for APAP-induced liver injury. Our study confirmed the important role of RIP1 kinase activity in APAP-induced acute liver failure.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Falência Hepática Aguda , Acetaminofen/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Hepatócitos , Fígado , Camundongos , Camundongos Endogâmicos C57BL
4.
Free Radic Biol Med ; 172: 578-589, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34242792

RESUMO

Acetaminophen (APAP) is the leading cause of acute liver failure (ALF), which is characterized by GSH depletion, oxidative stress and mitochondrial dysfunction. However, the specific mechanism of APAP-induced ALF remains to be clarified. In this study, we demonstrated that indoleamine 2,3-dioxygenase 1 (IDO1) aggravated APAP-induced ALF associated with excess lipid peroxidation, which was reversed by lipid peroxidation inhibitor (ferrostatin-1). Meanwhile, IDO1 deficiency effectively decreased the accumulation of reactive nitrogen species. Additionally, IDO1 deficiency prevented against APAP-induced liver injury through suppressing the activation of macrophages, thereby reduced their iron uptake and export, eventually reduced iron accumulation in hepatocytes through transferrin and transferrin receptor axis. In summary, our study confirmed that APAP-induced IDO1 aggravated ALF by triggering excess oxidative and nitrative stress and iron accumulation in liver. These results offer new insights for the clinical treatment of ALF or iron-dysregulated liver diseases in the future.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Dioxigenases , Falência Hepática Aguda , Acetaminofen/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Dioxigenases/metabolismo , Hepatócitos , Ferro/metabolismo , Fígado/metabolismo , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo
5.
Toxicol Sci ; 183(1): 154-169, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34129049

RESUMO

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-adenosine diphosphate (ADP)-ribose polymerase (TIPARP/PARP7), an aryl hydrocarbon receptor (AHR) target gene and mono-ADP-ribosyltransferase, acts as part of a negative feedback loop to repress AHR signaling. This process is prevented by a single H532A mutation in TIPARP that destroys its catalytic activity. We hypothesized that the loss of TIPARP catalytic activity would increase sensitivity to TCDD-induced toxicity in vivo. To test this, we created a catalytically deficient mouse line (TiparpH532A) by introducing a single H532A mutation in TIPARP. Treatment of mouse embryonic fibroblasts or hepatocytes isolated from TiparpH532A mice confirmed the increased TCDD-induced expression of the AHR target genes Cyp1a1, Cyp1b1, and Tiparp. TiparpH532A mice given a single injection of 10 µg/kg TCDD, a nonlethal dose in Tiparp+/+ mice, did not survive beyond day 10. All Tiparp+/+ mice survived the 30-day treatment. TCDD-treated TiparpH532A mice displayed increased expression of AHR target genes, increased steatohepatitis and hepatotoxicity. Hepatic RNA-sequencing revealed 7-fold more differentially expressed genes in TiparpH532A mice than in Tiparp+/+ mice (4542 vs 647 genes) 6 days after TCDD treatment. Differentially expressed genes included genes involved in xenobiotic metabolism, lipid homeostasis and inflammation. Taken together, these data further support TIPARP as a critical negative regulator of AHR activity and show that loss of its catalytic activity is sufficient to increase sensitivity to TCDD-induced steatohepatitis and lethality. Since TIPARP inhibition has recently emerged as a potential anticancer therapy, the impact on AHR signaling, TCDD and polycyclic aromatic hydrocarbon toxicity will need to be carefully considered under conditions of therapeutic TIPARP inhibition.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Dibenzodioxinas Policloradas , Adenosina Difosfato Ribose , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Fibroblastos , Camundongos , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/genética
6.
Toxicology ; 458: 152838, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34153373

RESUMO

N,N-dimethylformamide (DMF) is an organic compound widely used in industrial production processes as a solvent with a low evaporation rate. Excessive exposure to DMF may lead to liver damage. Oxidative stress has been reported as one of the main causes of DMF-induced hepatotoxicity. Several doses of DMF (0, 1, 5, and 10 mM) were used to treat HL-7702 cells for a relatively long period to simulate the actual exposure pattern in occupational settings, and oxidative stress was induced. Previous studies illustrated that circular RNA (circRNA) plays a vital role in sustaining hepatocyte physiological function. To explore whether aberrant circRNA expression is involved in DMF-induced excessive ROS generation and hepatotoxicity, high-throughput transcriptional sequencing was performed to identify the altered circRNA expression profiles in HL-7702 liver cells after treatment with 0, 75, or 150 mM DMF for 48 h. We found that levels of induced oxidative stress were similar to those in the long-term exposure model. Among the altered circRNAs, one circRNA (hsa_circ_0005915) was significantly upregulated after DMF exposure, and it affected DMF-mediated oxidative stress in HL-7702 cells. Further experiments revealed that hsa_circ_0005915 downregulated the expression of nuclear factor erythoid-2-related factor 2 (NRF2) at the post-transcriptional level via promoting the ubiquitination and degradation of NRF2, which led to the increase of ROS accumulation. Further investigation demonstrated that the expression levels of NRF2-regulated antioxidative genes-heme oxygenase 1 (HO1) and NAD(P)H quinone dehydrogenase 1 (NQO1)-indeed declined after the overexpression of hsa_circ_0005915. In vivo study also indicated that DMF exposure can upregulate the expression of mmu_circ_0007941 (homologous circRNA of hsa_circ_0005915) and downregulated Nrf2 and Ho1 proteins. In summary, our results revealed that hsa_circ_0005915 plays an important role in promoting DMF-induced oxidative stress by inhibiting the transcriptional activity of the NRF2/ARE axis, which provides a potential molecular mechanism of DMF-mediated hepatotoxicity.


Assuntos
Dimetilformamida/toxicidade , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , RNA Circular/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , MicroRNAs , NAD(P)H Desidrogenase (Quinona)/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima
7.
Toxicology ; 458: 152839, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34153374

RESUMO

Toxicological effects of chemicals are mostly tested individually. However, consumers encounter exposure to complex mixtures, for example multiple pesticide residues, by consuming food such as crops, fruits or vegetables. Currently, more than 450 active substances are approved in the European Union, and there is little data on effects after combined exposure to several pesticides. Toxicological animal studies would increase enormously, if pesticide combinations had to be analyzed in vivo. Therefore, in vitro methods addressing this issue are needed. We have developed 32 immunoaffinity-based mass spectrometry assays to investigate the impact of hepatotoxic active substances on liver proteins in human HepaRG cells. Five compounds were selected based on their (dis)similar capability to modulate protein levels, and on their combined use in commercially available formulations. Four binary mixtures were prepared from these five substances and tested in different concentrations over three time points. We applied a novel statistical method to describe deviations from additivity and to detect antagonistic and synergistic effects. The results regarding the abundance of hepatotoxicity-related proteins showed additive behavior for 1323 out of 1427 endpoints tested, while 104 combinatorial effects deviating from additivity, such as antagonism or synergism were observed.


Assuntos
Fígado/metabolismo , Praguicidas/toxicidade , Proteínas/metabolismo , Alternativas aos Testes com Animais , Biomarcadores , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/genética , Misturas Complexas , Interações Medicamentosas , Sinergismo Farmacológico , Perfilação da Expressão Gênica , Humanos , Fígado/efeitos dos fármacos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Testes de Toxicidade/métodos
8.
Int J Biol Macromol ; 185: 306-316, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34166692

RESUMO

The study was aimed to investigate the simulated digestion behavior of the bioactive polysaccharides from Chimonanthus nitens Oliv (COP1), antioxidant activity in vitro, and prevention against cyclophosphamide (CP) induced oxidative damage in mice. The results showed that COP1 were 18.843 kDa, and consisted of arabinose (56.6 mol%), galactose (24.9 mol%), xylose (11.1 mol%), and glucose (7.4 mol%). Gastrointestinal digestion significantly improved the radical (DPPH, OH, and ABTS+) scavenging activities of COP1. Meanwhile, administration of COP1 (150, 300, and 600 mg/kg, continuous 16 days) prevented hepatotoxicity in CP-induced mice (reducing liver index and transaminase levels, alleviating liver damage). COP1 also attenuated oxidative stress as evident from as shown by reduced levels of MDA and enhanced activity of antioxidant enzymes (CAT, SOD, and GSH-Px). In addition, COP1 regulated the Nrf2/Keap1 signaling pathway in CP-treated mice, decreasing the upstream factor Keap1 and increasing the upstream factor Nrf2, which in turn enhanced the expression of downstream factors (NQO1, HO-1, GSH-Px, SOD1, and CAT). COP1 also protected the body from CP-induced oxidative damage by down-regulating Bax and caspase3 in the apoptosis pathway and up-regulating Bcl-2 mRNA levels. Overall, COP1 might be harnessed as an effective natural antioxidant for medical and food industries.


Assuntos
Antioxidantes/administração & dosagem , Calycanthaceae/química , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Ciclofosfamida/efeitos adversos , Polissacarídeos/administração & dosagem , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hospedeiro Imunocomprometido , Malondialdeído/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/química , Polissacarídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos
9.
Int J Biol Macromol ; 185: 338-349, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34171250

RESUMO

Chemical liver injury threatens seriously human health, along with the shortage of efficiency and low-toxicity drugs. Herein, the novel oral nanocomplexes composed of deoxycholic acid-grafted chitosan and oleanolic acid were constructed to reverse the CCl4-induced acute liver damage in mice. Results indicated core-shell nanocomplexes, maintained by the hydrophobic interaction between deoxycholic acid and oleanolic acid, could be dissociated in the intestine. Notably, the nanocomplexes possessed superior hepatoprotective effect in vivo, possibly due to the synergistic effect between grafted chitosan and oleanolic acid. Mechanism investigations suggested that nanocomplexes reversed CCl4-induced liver injury through improving hepatic antioxidant capacity via NrF2/Keap1 pathway and regulating inflammation response via NF-κB signaling pathway. The novel oral nanocomplexes represent an effective strategy for chemical liver injury therapy.


Assuntos
Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Quitosana/química , Ácido Desoxicólico/química , Ácido Oleanólico/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Nanocompostos , Ácido Oleanólico/química , Ácido Oleanólico/farmacocinética , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
10.
Toxicology ; 458: 152832, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34107285

RESUMO

Diphenylamine NSAIDs are highly prescribed therapeutics for chronic pain despite causing symptomatic hepatotoxicity through mitochondrial damage in five percent of patients taking them. Differences in toxicity are attributed to structural modifications to the diphenylamine scaffold rather than its inherent toxicity. We hypothesize that marketed diphenylamine NSAID substituents affect preference and efficiency of bioactivation pathways and clearance. We parsed the FDA DILIrank hepatotoxicity database and modeled marketed drug bioactivation into quinone-species metabolites to identify a family of seven clinically relevant diphenylamine NSAIDs. These drugs fell into two subgroups, i.e., acetic acid and propionic acid diphenylamines, varying in hepatotoxicity risks and modeled bioactivation propensities. We carried out steady-state kinetic studies to assess bioactivation pathways by trapping quinone-species metabolites with dansyl glutathione. Analysis of the glutathione adducts by mass spectrometry characterized structures while dansyl fluorescence provided quantitative yields for their formation. Resulting kinetics identified four possible bioactivation pathways among the drugs, but reaction preference and efficiency depended upon structural modifications to the diphenylamine scaffold. Strikingly, diphenylamine dihalogenation promotes formation of quinone metabolites through four distinct metabolic pathways with high efficiency, whereas those without aromatic halogen atoms were metabolized less efficiently through two or fewer metabolic pathways. Overall metabolism of the drugs was comparable with bioactivation accounting for 4-13% of clearance. Lastly, we calculated daily bioload exposure of quinone-species metabolites based on bioactivation efficiency, bioavailability, and maximal daily dose. The results revealed stratification into the two subgroups; propionic acid diphenylamines had an average four-fold greater daily bioload compared to acetic acid diphenylamines. However, the lack of sufficient study on the hepatotoxicity for all drugs prevents further correlative analyses. These findings provide critical insights on the impact of diphenylamine bioactivation as a precursor to hepatotoxicity and thus, provide a foundation for better risk assessment in drug discovery and development.


Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Difenilamina/química , Difenilamina/metabolismo , Ácido Acético/metabolismo , Ativação Metabólica , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Disponibilidade Biológica , Doença Hepática Induzida por Substâncias e Drogas/genética , Bases de Dados Factuais , Difenilamina/toxicidade , Glutationa/metabolismo , Halogenação , Humanos , Cinética , Microssomos Hepáticos/metabolismo , Propionatos/metabolismo , Quinonas/metabolismo
11.
Toxicol Sci ; 183(1): 1-13, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34086958

RESUMO

Drug-induced liver injury (DILI) is a significant clinical issue, affecting 1-1.5 million patients annually, and remains a major challenge during drug development-toxicity and safety concerns are the second-highest reason for drug candidate failure. The future prevalence of DILI can be minimized by developing a greater understanding of the biological mechanisms behind DILI. Both qualitative and quantitative analytical techniques are vital to characterizing and investigating DILI. In vitro assays are capable of characterizing specific aspects of a drug's hepatotoxic nature and multiplexed assays are capable of characterizing and scoring a drug's association with DILI. However, an even deeper insight into the perturbations to biological pathways involved in the mechanisms of DILI can be gained through the use of omics-based analytical techniques: genomics, transcriptomics, proteomics, and metabolomics. These omics analytical techniques can offer qualitative and quantitative insight into genetic susceptibilities to DILI, the impact of drug treatment on gene expression, and the effect on protein and metabolite abundance. This review will discuss the analytical techniques that can be applied to characterize and investigate the biological mechanisms of DILI and potential predictive biomarkers.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Biomarcadores , Doença Hepática Induzida por Substâncias e Drogas/genética , Genômica , Humanos , Fígado , Metabolômica , Proteômica
12.
Ann Palliat Med ; 10(6): 6518-6534, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34154362

RESUMO

BACKGROUND: Isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB) are the four most common drugs for the first-line treatment of tuberculosis (TB). Although chemotherapy drugs are widely used in the treatment of TB, and achieved good results, but the side effects, especially anti-tuberculosis drug-induced liver injury (ATDILI), cannot be overlooked. Many researchers have made efforts to uncover the association of cytochrome P450 (CYP) enzyme genetic polymorphisms with ATDILI. In this study, we systematically reviewed and meta-analyzed the relationship between CYP polymorphism and susceptibility to ATDILI. METHODS: We carried out literature searches of PubMed, Ovid, the Cochrane Library, Web of Science and Chinese National Knowledge Infrastructure (CNKI). Medical Subject Headings (MeSH) terms including "cytochrome P450 enzyme", "drug-induced liver injury", "polymorphism", "tuberculosis", and "hepatotoxicity" were used as keywords for our searches. RESULTS: The pooled odds ratio (OR) of all studies for CYP2E1 to the risk of ATDILI was 1.18 [95% confidence interval (CI): 0.82-1.71]. The articles in this meta-analysis were observed to be mildly heterogeneous. Further subgroup analysis revealed that the patients who receiving a four-drug protocol (INH + RIF + PZA + EMB) or three-drug protocol (INH + RIF + PZA) regimens showed a higher risk of ATDILI than those who receiving INH alone. However, subgroup analyses according to participants' ethnic origin, study type, and the definition of ATDILI produced no statistically significant results. Associations between other genes in the CYP family and ATDILI were indistinct and equivocal. DISCUSSION: Our meta-analysis has uncovered an association between CYP2E1 RsaI/PstI polymorphisms and ATDILI, especially among patients who receive a four-drug (INH + RIF + PZA + EMB) or three-drug (INH + RIF + PZA) anti-TB treatment regimen.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Tuberculose , Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/genética , Sistema Enzimático do Citocromo P-450/genética , Humanos , Polimorfismo Genético/genética , Tuberculose/tratamento farmacológico
13.
Int J Mol Sci ; 22(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068678

RESUMO

The liver is among the most frequently targeted organs by noxious chemicals of diverse nature. Liver toxicity testing using laboratory animals not only raises serious ethical questions, but is also rather poorly predictive of human safety towards chemicals. Increasing attention is, therefore, being paid to the development of non-animal and human-based testing schemes, which rely to a great extent on in vitro methodology. The present paper proposes a rationalized tiered in vitro testing strategy to detect liver toxicity triggered by chemicals, in which the first tier is focused on assessing general cytotoxicity, while the second tier is aimed at identifying liver-specific toxicity as such. A state-of-the-art overview is provided of the most commonly used in vitro assays that can be used in both tiers. Advantages and disadvantages of each assay as well as overall practical considerations are discussed.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/genética , Técnicas In Vitro/tendências , Fígado/efeitos dos fármacos , Testes de Toxicidade/tendências , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Humanos , Modelos Animais , Medição de Risco
14.
J Agric Food Chem ; 69(27): 7619-7628, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34156842

RESUMO

This research assessed the anti-inflammatory and hepatoprotective properties of inosine and the associated mechanism. Inosine pretreatment significantly reduced the secretion of several inflammatory factors and serum alanine transaminase (ALT) and aspartate amino transferase (AST) levels in a dose-dependent manner compared with the lipopolysaccharide (LPS) group. In LPS-treated mice, inosine pretreatment significantly reduced the ALT and malondialdehyde (MDA) concentration and significantly elevated the antioxidant enzyme activity. Furthermore, inosine pretreatment significantly altered the relative abundance of the genera, Bifidobacterium, Lachnospiraceae UCG-006, and Muribaculum. Correlation analysis showed that Bifidobacterium and Lachnospiraceae UCG-006 were positively related to the cecal short-chain fatty acids but negatively related to the serum IL-6 and hepatic AST and ALT levels. Notably, inosine pretreatment significantly modulated the hepatic TLR4, MYD88, NF-κB, iNOS, COX2, AMPK, Nfr2, and IκB-α expression. These results suggested that inosine pretreatment alters the intestinal microbiota structure and improves LPS-induced acute liver damage and inflammation through modulating the TLR4/NF-κB signaling pathway.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Microbiota , Animais , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/genética , Inflamação/tratamento farmacológico , Inosina , Lipopolissacarídeos/efeitos adversos , Fígado , Camundongos , NF-kappa B/genética , Receptor 4 Toll-Like/genética
15.
Toxicol Sci ; 182(2): 327-345, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-33983442

RESUMO

An acetaminophen (APAP) overdose is the most common cause of acute liver failure in the United States. A hallmark characteristic of APAP hepatotoxicity is centrilobular necrosis. General, innate mechanisms such as lower amounts of GSH and higher cytochrome P450 2e1 expression in pericentral (PC) hepatocytes are known to contribute to the differences in susceptibility to cell injury between periportal (PP) hepatocytes and PC hepatocytes. Although a sequence of molecular events involving formation of the reactive metabolite N-acetyl-p-benzoquinone imine, GSH depletion, oxidative stress, and c-Jun N-terminal kinase activation define the early cell stress trajectory following APAP exposure, their activation in PC versus PP hepatocytes is not well characterized. By using single-cell RNA-sequencing, we provide the first reconstruction of the early transcriptomic APAP liver lobule after validation of our methodology using human liver single-cell RNA-sequencing data. Two hours after APAP treatment, we find that PP hepatocytes progress along the APAP stress axis to oxidative stress, before resolving injury due to innate and adaptive mechanisms. However, PC hepatocytes continue along this stress axis as indicated by activation of mitogen-activated protein kinase genes, which is absent in PP hepatocytes. We also identify a population of glutamine synthetase enriched PC hepatocytes in close proximity to the central vein, where a stepwise induction of a stress program culminated in cell death. Collectively, these findings elucidate a molecular sequence of events distinguishing the differential response to APAP exposure between PP and PC hepatocytes and identify a subset of uniquely susceptible PC hepatocytes.


Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Acetaminofen/metabolismo , Acetaminofen/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Glutationa/metabolismo , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , RNA/metabolismo , Transcriptoma
16.
Clin Chim Acta ; 519: 153-162, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33932406

RESUMO

BACKGROUND AND AIMS: To assess the relevance of the slow acetylator phenotype based on NAT2 genotypes, among patients with pulmonary tuberculosis (PTB) that developed hepatotoxicity after first-line tuberculosis treatment in a Northeastern Mexican population. METHODS: Ninety one PTB patients were included, 7 of them developed hepatotoxicity. NAT2 SNPs (rs1801279, rs1041983, rs1801280, rs1799929, rs1799930, rs1208, and rs1799931) were genotyped by TaqMan allelic discrimination assay. Statistical analyses were performed using Epi Info statistical software 7.0 and SHEsisPlus for haplotype reconstruction. The NAT2 slow non-synonymous SNP were studied by molecular dynamic analysis (MDA). RESULTS: The frequency of the haplotype associated with slow acetylation status for PTB was 58%, and for with hepatotoxicity (PTB-H) represented 42.6%. Three haplotypes, NAT2*5Q, NAT2*5U, NAT2*5Va were exclusively present in seven PTB-H patients, (P = 0.01, P = 0.0006, P = 0.01, respectively). These haplotypes include the combination of two SNPs (I114T + R197Q or I114T + G286E). The effect of the SNPs on protein structure is to disrupt the CoA binding site affecting acetylation activity. CONCLUSION: Our study provides insight into slow acetylation NAT2 haplotypes associated with hepatotoxicity after first-line tuberculosis treatment, for first time, in a Mexican population. The molecular mechanism acts at the CoA binding site.


Assuntos
Arilamina N-Acetiltransferase , Doença Hepática Induzida por Substâncias e Drogas , Tuberculose , Antituberculosos/efeitos adversos , Arilamina N-Acetiltransferase/genética , Arilamina N-Acetiltransferase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Genótipo , Humanos , Estrutura Molecular , Polimorfismo de Nucleotídeo Único , Tuberculose/tratamento farmacológico , Tuberculose/genética
17.
Liver Int ; 41(8): 1884-1893, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33899326

RESUMO

BACKGROUND/AIMS: Allopurinol can cause HLA class I-associated life-threatening severe skin reactions. However, HLA risk and association with clinical features in allopurinol hepatotoxicity are unknown. METHODS: Eleven of 17 patients with suspected allopurinol hepatotoxicity enrolled into the Drug-Induced Liver Injury Network were adjudicated as definite, highly likely, or probable. High-resolution HLA sequencing was undertaken in cases and compared with population and other DILI controls. RESULT: Median age was 60 years, 54% were male, and 63% African- American, 27% Caucasian, and 9% Hispanic. Patients presented at a median of 52 days after starting allopurinol, all were hospitalized and six were jaundiced. The median peak ALT, alkaline phosphatase, and total bilirubin were 525 U/L, 521 U/L, and 7.8 mg/dl, respectively, with a median R ratio of 2.7 at onset. During follow-up, nine patients were treated with corticosteroids including five of the six with suspected DRESS. Three patients died including two from liver failure at 38 and 45 days after onset, and the remaining eight recovered. Three HLA alleles were found to be overrepresented in allopurinol cases, particularly in African Americans: HLA-B*58:01, which has been previously linked to severe skin reactions, and HLA-B*53:01 and HLA-A*34:02, all of which are more frequently found in African Americans than European Americans or Latinos. CONCLUSIONS: Allopurinol hepatotoxicity is associated with systemic hypersensitivity, a short latency to onset, African-American race and three HLA risk alleles, HLA-B*58:01, HLA-B*53:01, and HLA-A*34:02-58:01 testing may help confirm a diagnosis of hepatotoxicity in allopurinol-treated patients.


Assuntos
Alopurinol , Doença Hepática Induzida por Substâncias e Drogas , Alelos , Alopurinol/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/genética , Antígenos HLA-B/genética , Antígenos de Histocompatibilidade Classe I , Humanos , Masculino , Pessoa de Meia-Idade
18.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925355

RESUMO

Drug-induced liver injury (DILI) is a challenging clinical event in medicine, particularly because of its ability to present with a variety of phenotypes including that of autoimmune hepatitis or other immune mediated liver injuries. Limited diagnostic and therapeutic tools are available, mostly because its pathogenesis has remained poorly understood for decades. The recent scientific and technological advancements in genomics and immunology are paving the way for a better understanding of the molecular aspects of DILI. This review provides an updated overview of the genetic predisposition and immunological mechanisms behind the pathogenesis of DILI and presents the state-of-the-art experimental models to study DILI at the pre-clinical level.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Predisposição Genética para Doença/genética , Hepatite Autoimune/imunologia , Humanos , Imunogenética/métodos , Fígado/patologia , Modelos Teóricos , Fenótipo , Fatores de Risco
19.
J Biochem Mol Toxicol ; 35(6): 1-15, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33788351

RESUMO

Esculentoside A (EsA) is a kind of triterpenoid saponins from the root tuber of Phytolacca acinosa Roxb. It has extensive medicinal activity, such as antibacterial, anti-inflammatory, immune regulation, and cell proliferation inhibition. However, some researches suggested that EsA can cause hepatotoxicity, whose mechanism is not precise. To ensure the safety and reliability in the clinical use of Phytolacca acinosa Roxb., it is necessary to establish a rapid and accurate method to evaluate the toxicity, analyze and verify the toxicity mechanism of EsA. Therefore, this research explored the mechanism of hepatotoxicity induced by EsA in rats and analyzed endogenous metabolites' changes in rat plasma by combining network toxicology with non-targeted metabolomics. We obtained 58 critical targets of EsA induced hepatotoxicity in rats based on the strategy of network toxicology, including albumin, mitogen-activated protein kinase 1, Caspase-3, etc. Many important pathways were obtained by Kyoto Encyclopedia of Genes and Genomes enrichment analysis, such as HIF-1 signaling pathway, TNF signaling pathway, IL-17 signaling pathway, and other concerning pathways. Sixteen biomarkers, including 5-hydroxykynurenamine, N-acetylserotonin, palmitic acid, etc., were screened from rat plasma using Ultra-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC-Q-TOF/MS), mainly involve Glycerophospholipid metabolism, Tryptophan metabolism, and other metabolic pathways. Further analysis showed that EsA may induce liver injury by activating oxidative stress and energy metabolism disorders, triggering inflammation and apoptosis.


Assuntos
Bases de Dados de Ácidos Nucleicos , Redes e Vias Metabólicas , Metabolômica , Ácido Oleanólico/análogos & derivados , Saponinas/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Masculino , Ácido Oleanólico/toxicidade , Ratos , Ratos Wistar
20.
Am J Chin Med ; 49(3): 705-718, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33657990

RESUMO

Acetaminophen (APAP) overdose is the leading cause of acute liver failure (ALF) in the Western world, with limited treatment opportunities. 3,5,7,4[Formula: see text]-Tetrahydroxyflavanone (Dihydrokaempferol, DHK, Aromadendrin) is a flavonoid isolated from Chinese herbs and displays high anti-oxidant and anti-inflammatory capacities. In this study, we investigated the protective effect by DHK against APAP-induced liver injury in vitro and in vivo and the potential mechanism of action. Cell viability assays were used to determine the effects of DHK against APAP-induced liver injury. The levels of reactive oxygen species (ROS), serum alanine/aspartate aminotransferases (ALT/AST), liver myeloperoxidase (MPO), and malondialdehyde (MDA) were measured and analyzed to evaluate the effects of DHK on APAP-induced liver injury. Western blotting, immunofluorescence staining, RT-PCR, and Transmission Electron Microscope were carried out to detect the signaling pathways affected by DHK. Here, we found that DHK owned a protective effect on APAP-induced liver injury with a dose-dependent manner. Meanwhile, Western blotting showed that DHK promoted SIRT1 expression and autophagy, activated the NRF2 pathway, and inhibited the translocation of nuclear p65 (NF-[Formula: see text]B) in the presence of APAP. Furthermore, SIRT1 inhibitor EX-527 aggravated APAP-induced hepatotoxicity when treating with DHK. Molecular docking results suggested potential interaction between DHK and SIRT1. Taken together, our study demonstrates that DHK protects against APAP-induced liver injury by activating the SIRT1 pathway, thereby promoting autophagy, reducing oxidative stress injury, and inhibiting inflammatory responses.


Assuntos
Acetaminofen/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Fitoterapia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sirtuína 1/metabolismo , Alanina Transaminase/metabolismo , Anti-Inflamatórios , Antioxidantes , Aspartato Aminotransferases/metabolismo , Autofagia/efeitos dos fármacos , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/química , Flavonoides/isolamento & purificação , Expressão Gênica/efeitos dos fármacos , Humanos , Malondialdeído/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/genética
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