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[PMID]:28935588
[Au] Autor:Kindrat I; Dreval K; Shpyleva S; Tryndyak V; de Conti A; Mudalige TK; Chen T; Erstenyuk AM; Beland FA; Pogribny IP
[Ad] Endereço:Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, United States; Department of Biological and Medical Chemistry, Ivano-Frankivsk National Medical University, Ivano-Frankivsk, Ukraine.
[Ti] Título:Effect of methapyrilene hydrochloride on hepatic intracellular iron metabolism in vivo and in vitro.
[So] Source:Toxicol Lett;281:65-73, 2017 Nov 05.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The liver, a central detoxification organ and main regulator of systemic iron homeostasis, is prone to damage by xenobiotics. In the present study, we investigated the effect of the hepatotoxicant and hepatocarcinogen methapyrilene hydrochloride on iron metabolism in rat liver in a repeat-dose in vivo toxicity study and in human HepaRG cells in vitro. Treatment of male Fischer 344 (F344) rats with methapyrilene at doses 40 and 80mg/kg body weight (bw)/day by gavage for 6 weeks resulted in changes in the expression of classic hepatotoxicity-related marker genes and iron homeostasis-related genes, especially a prominent, dose-dependent down-regulation of the transferrin (Tf) gene and an up-regulation of the ferritin, light chain (Ftl) gene. A decrease in the level of TF and an increase in the level of FTL also occurred in methapyrilene-treated differentiated HepaRG cells, indicating the existence of interspecies and in vitro-in vivo similarities in the disturbance of cellular iron homeostasis upon liver injury. In contrast, there was minimal overlap in the expression of liver toxicity-marker genes in the livers of rats and in HepaRG cells treated with methapyrilene. Importantly, the decrease of transferrin at mRNA and protein levels occurred after the treatment with a low dose of methapyrilene that exhibited minimal cytotoxicity. These results demonstrate the significance of the dysregulation of hepatic iron metabolism in the pathogenesis and mechanism of chemical-induced liver toxicity and suggest that these changes may be sensitive and useful indicators of potentially hepatotoxic chemicals.
[Mh] Termos MeSH primário: Ferro/metabolismo
Fígado/efeitos dos fármacos
Metapirileno/toxicidade
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Relação Dose-Resposta a Droga
Regulação para Baixo
Ferritinas/genética
Ferritinas/metabolismo
Marcadores Genéticos
Hepatócitos/efeitos dos fármacos
Hepatócitos/metabolismo
Fígado/metabolismo
Masculino
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Ratos
Ratos Endogâmicos F344
Transferrina/genética
Transferrina/metabolismo
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Genetic Markers); 0 (RNA, Messenger); 0 (Transferrin); 9007-73-2 (Ferritins); A01LX40298 (Methapyrilene); E1UOL152H7 (Iron)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170923
[St] Status:MEDLINE


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[PMID]:28552552
[Au] Autor:Leitch AC; Probert PME; Shayman JA; Meyer SK; Kass GEN; Wright MC
[Ad] Endereço:Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle Upon Tyne, UK.
[Ti] Título:B-13 progenitor-derived hepatocytes (B-13/H cells) model lipid dysregulation in response to drugs and chemicals.
[So] Source:Toxicology;386:120-132, 2017 Jul 01.
[Is] ISSN:1879-3185
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Lipid dysregulation is a common hepatic adverse outcome after exposure to toxic drugs and chemicals. A donor-free rat hepatocyte-like (B-13/H) cell was therefore examined as an in vitro model for investigating mechanisms. The B-13/H cell irreversibly accumulated triglycerides (steatosis) in a time- and dose-dependent manner when exposed to fatty acids, an effect that was potentiated by the combined addition of hyperglycaemic levels of glucose and insulin. B-13/H cells also expressed the LXR nuclear receptors and exposure to their activators - T0901317 or GW3965 - induced luciferase expression from a transfected LXR-regulated reporter gene construct and steatosis in a dose-dependent manner with T0901317. Exposing B-13/H cells to a variety of cationic amphiphilic drugs - but not other hepatotoxins - also resulted in a time- and dose-dependent accumulation of phospholipids (phospholipidosis), an effect that was reduced by over-expression of lysosomal phospholipase A2. Through application of this model, hepatotoxin methapyrilene exposure was shown to induce phospholipidosis in both B-13 and B-13/H cells in a time- and dose-dependent manner. However, methapyrilene was only toxic to B-13/H cells and inhibitors of hepatotoxicity enhanced phospholipidosis, suggesting phospholipidosis is not a pathway in toxicity for this withdrawn drug. In contrast, pre-existing steatosis had minimal effect on methapyrilene hepatotoxicity in B-13/H cells. These data demonstrate that the donor free B-13 cell system for generating hepatocyte-like cells may be employed in studies of fatty acid- and LXR activator-induced steatosis and phospholipidosis and in the dissection of pathways leading to adverse outcomes such as hepatotoxicity.
[Mh] Termos MeSH primário: Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia
Ácidos Graxos/metabolismo
Hepatócitos/efeitos dos fármacos
Metabolismo dos Lipídeos/efeitos dos fármacos
Triglicerídeos/metabolismo
[Mh] Termos MeSH secundário: Animais
Benzoatos/administração & dosagem
Benzoatos/toxicidade
Benzilaminas/administração & dosagem
Benzilaminas/toxicidade
Linhagem Celular
Doença Hepática Induzida por Substâncias e Drogas/etiologia
Relação Dose-Resposta a Droga
Fígado Gorduroso/metabolismo
Hepatócitos/metabolismo
Hidrocarbonetos Fluorados/administração & dosagem
Hidrocarbonetos Fluorados/toxicidade
Receptores X do Fígado/metabolismo
Metapirileno/administração & dosagem
Metapirileno/toxicidade
Fosfolipídeos/metabolismo
Ratos
Sulfonamidas/administração & dosagem
Sulfonamidas/toxicidade
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoates); 0 (Benzylamines); 0 (Fatty Acids); 0 (GW 3965); 0 (Hydrocarbons, Fluorinated); 0 (Liver X Receptors); 0 (Phospholipids); 0 (Sulfonamides); 0 (TO-901317); 0 (Triglycerides); A01LX40298 (Methapyrilene)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170826
[Lr] Data última revisão:
170826
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170530
[St] Status:MEDLINE


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[PMID]:28529062
[Au] Autor:Slopianka M; Herrmann A; Pavkovic M; Ellinger-Ziegelbauer H; Ernst R; Mally A; Keck M; Riefke B
[Ad] Endereço:Bayer AG, Investigational Toxicology, Muellerstraße 178, 13353 Berlin, Germany; University Wuerzburg, Department of Toxicology, Versbacher Straße 9, 97078 Wuerzburg, Germany. Electronic address: markus.slopianka@bayer.com.
[Ti] Título:Quantitative targeted bile acid profiling as new markers for DILI in a model of methapyrilene-induced liver injury in rats.
[So] Source:Toxicology;386:1-10, 2017 Jul 01.
[Is] ISSN:1879-3185
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Recently, bile acids (BAs) were reported as promising markers for drug-induced liver injury (DILI). BAs have been suggested to correlate with hepatocellular and hepatobiliary damage; however a clear connection of BA patterns with different types of DILI remains to be established. To investigate if BAs can improve the assessment of liver injury, 20 specific BAs were quantitatively profiled via LC-MS/MS in plasma and liver tissue in a model of methapyrilene-induced liver injury in rats. Methapyrilene, a known hepatotoxin was dosed daily over 14-days at doses of 30 and 80mg/kg, followed by a recovery phase of 10days. Conventional preclinical safety endpoints were related to BA perturbations and to hepatic gene expression profiling for a mechanistic interpretation of effects. Histopathological signs of hepatocellular and hepatobiliary damage with significant changes of clinical chemistry markers were accompanied by significantly increased levels of indivdual BAs in plasma and liver tissue. BA perturbations were already evident at the earliest time point after 30mg/kg treatment, and thereby indicating better sensitivity than clinical chemistry parameters. Furthermore, the latter markers suggested recovery of liver injury, whereas BA levels in plasma and liver remained significantly elevated during the recovery phase, in line with persistent histopathological findings of bile duct hyperplasia (BDH) and bile pigment deposition. Gene expression profiling revealed downregulation of genes involved in BA synthesis (AMACR, BAAT, ACOX2) and hepatocellular uptake (NTCP, OATs), and upregulation for efflux transporters (MRP2, MRP4), suggesting an adaptive hepatocellular protection mechanism against cytotoxic bile acid accumulation. In summary, our data suggests that specific BAs with high reliability such as cholic acid (CA) and chenodeoxycholic acid (CDCA) followed by glycocholic acid (GCA), taurocholic acid (TCA) and deoxycholic acid (DCA) can serve as additional biomarkers for hepatocellular/hepatobiliary damage in the liver in rat toxicity studies.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/metabolismo
Biomarcadores/metabolismo
Doença Hepática Induzida por Substâncias e Drogas/etiologia
Fígado/efeitos dos fármacos
Metapirileno/toxicidade
[Mh] Termos MeSH secundário: Animais
Doença Hepática Induzida por Substâncias e Drogas/patologia
Cromatografia Líquida
Relação Dose-Resposta a Droga
Regulação para Baixo/efeitos dos fármacos
Regulação da Expressão Gênica/efeitos dos fármacos
Fígado/patologia
Masculino
Metapirileno/administração & dosagem
Ratos
Ratos Wistar
Reprodutibilidade dos Testes
Espectrometria de Massas em Tandem
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (Biomarkers); A01LX40298 (Methapyrilene)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170523
[St] Status:MEDLINE


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[PMID]:26946349
[Au] Autor:Verstraelen S; Peers B; Maho W; Hollanders K; Remy S; Berckmans P; Covaci A; Witters H
[Ad] Endereço:VITO NV, Applied Bio & Molecular Systems, Boeretang 200, B-2400, Mol, Belgium.
[Ti] Título:Phenotypic and biomarker evaluation of zebrafish larvae as an alternative model to predict mammalian hepatotoxicity.
[So] Source:J Appl Toxicol;36(9):1194-206, 2016 09.
[Is] ISSN:1099-1263
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Zebrafish phenotypic assays have shown promise to assess human hepatotoxicity, though scoring of liver morphology remains subjective and difficult to standardize. Liver toxicity in zebrafish larvae at 5 days was assessed using gene expression as the biomarker approach, complementary to phenotypic analysis and analytical data on compound uptake. This approach aimed to contribute to improved hepatotoxicity prediction, with the goal of identifying biomarker(s) as a step towards the development of transgenic models for prioritization. Morphological effects of hepatotoxic compounds (acetaminophen, amiodarone, coumarin, methapyrilene and myclobutanil) and saccharin as the negative control were assessed after exposure in zebrafish larvae. The hepatotoxic compounds induced the expected zebrafish liver degeneration or changes in size, whereas saccharin did not have any phenotypic adverse effect. Analytical methods based on liquid chromatography-mass spectrometry were optimized to measure stability of selected compounds in exposure medium and internal concentration in larvae. All compounds were stable, except amiodarone for which precipitation was observed. There was a wide variation between the levels of compound in the zebrafish larvae with a higher uptake of amiodarone, methapyrilene and myclobutanil. Detection of hepatocyte markers (CP, CYP3A65, GC and TF) was accomplished by in situ hybridization of larvae to coumarin and myclobutanil and confirmed by real-time reverse transcription-quantitative polymerase chain reaction. Experiments showed decreased expression of all markers. Next, other liver-specific biomarkers (i.e. FABP10a and NR1H4) and apoptosis (i.e. CASP-3 A and TP53) or cytochrome P450-related (CYP2K19) and oxidoreductase activity-related (ZGC163022) genes, were screened. Links between basic mechanisms of liver injury and results of biomarker responses are described. Copyright © 2016 John Wiley & Sons, Ltd.
[Mh] Termos MeSH primário: Marcadores Genéticos
Fígado/efeitos dos fármacos
Peixe-Zebra/genética
[Mh] Termos MeSH secundário: Acetaminofen/toxicidade
Amiodarona/toxicidade
Animais
Apoptose/efeitos dos fármacos
Hidrocarboneto de Aril Hidroxilases/genética
Hidrocarboneto de Aril Hidroxilases/metabolismo
Ceruloplasmina/genética
Ceruloplasmina/metabolismo
Cumarínicos/toxicidade
Feminino
Regulação da Expressão Gênica
Estudo de Associação Genômica Ampla
Seres Humanos
Hibridização In Situ
Larva/efeitos dos fármacos
Larva/genética
Fígado/metabolismo
Masculino
Metapirileno/toxicidade
Nitrilos/toxicidade
Oxirredutases N-Desmetilantes/genética
Oxirredutases N-Desmetilantes/metabolismo
Fenótipo
Testes de Toxicidade
Transferrina/genética
Transferrina/metabolismo
Triazóis/toxicidade
Proteínas de Peixe-Zebra/genética
Proteínas de Peixe-Zebra/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Coumarins); 0 (Genetic Markers); 0 (Nitriles); 0 (Transferrin); 0 (Triazoles); 0 (Zebrafish Proteins); 362O9ITL9D (Acetaminophen); A01LX40298 (Methapyrilene); A4VZ22K1WT (coumarin); B6T1JTM6KZ (systhane); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); EC 1.14.14.1 (cytochrome P-450 CYP3A65, zebrafish); EC 1.16.3.1 (Ceruloplasmin); EC 1.5.- (Oxidoreductases, N-Demethylating); N3RQ532IUT (Amiodarone)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160307
[St] Status:MEDLINE
[do] DOI:10.1002/jat.3288


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[PMID]:26558467
[Au] Autor:Kimura M; Mizukami S; Watanabe Y; Hasegawa-Baba Y; Onda N; Yoshida T; Shibutani M
[Ad] Endereço:Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology.
[Ti] Título:Disruption of spindle checkpoint function ahead of facilitation of cell proliferation by repeated administration of hepatocarcinogens in rats.
[So] Source:J Toxicol Sci;40(6):855-71, 2015 Dec.
[Is] ISSN:1880-3989
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:We aimed to clarify the hepatocarcinogen-specific disruption of cell cycle checkpoint functions and its time course after repeated administration of hepatocarcinogens. Thus, rats were repeatedly administered with hepatocarcinogens (methapyrilene, carbadox and thioacetamide), a marginal hepatocarcinogen (leucomalachite green), hepatocarcinogenic promoters (oxfendazole and ß-naphthoflavone) or non-carcinogenic hepatotoxicants (promethazine and acetaminophen) for 7, 28 or 90 days, and the temporal changes in cell proliferation, expression of G1/S and spindle checkpoint-related molecules, and apoptosis were examined using immunohistochemistry and/or real-time RT-PCR analysis. Hepatocarcinogens facilitating cell proliferation at day 28 of administration also facilitated cell proliferation and apoptosis at day 90. Hepatocarcinogen- or hepatocarcinogenic promoter-specific cellular responses were not detected by immunohistochemical single molecule analysis even after 90 days. Expression of Cdkn1a, Mad2l1, Chek1 and Rbl2 mRNA also lacked specificity to hepatocarcinogens or hepatocarcinogenic promoters. In contrast, all hepatocarcinogens and the marginally hepatocarcinogenic leucomalachite green induced Mdm2 upregulation or increase in the number of phosphorylated MDM2(+) cells from day 28, irrespective of the lack of cell proliferation facilitation by some compounds. However, different Tp53 expression levels suggest different mechanisms of induction or activation of MDM2 among hepatocarcinogens. On the other hand, hepatocarcinogenic methapyrilene and carbadox downregulated the number of both ubiquitin D(+) cells and proliferating cells remaining in M phase at day 28 and/or day 90, irrespective of the lack of cell proliferation facilitation in the latter. These results suggest that hepatocarcinogens disrupt spindle checkpoint function after 28 or 90 days of administration, which may be induced ahead of cell proliferation facilitation.
[Mh] Termos MeSH primário: Carbadox/toxicidade
Carcinógenos/administração & dosagem
Carcinógenos/toxicidade
Proliferação Celular/efeitos dos fármacos
Fígado/citologia
Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos
Metapirileno/toxicidade
Tioacetamida/toxicidade
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Apoptose/genética
Benzimidazóis/administração & dosagem
Benzimidazóis/toxicidade
Carbadox/administração & dosagem
Proliferação Celular/genética
Quinase do Ponto de Checagem 1
Inibidor de Quinase Dependente de Ciclina p21/genética
Inibidor de Quinase Dependente de Ciclina p21/metabolismo
Expressão Gênica/efeitos dos fármacos
Masculino
Metapirileno/administração & dosagem
Proteínas Quinases/genética
Proteínas Quinases/metabolismo
Ratos Endogâmicos F344
Corantes de Rosanilina/toxicidade
Fatores de Tempo
Ubiquitinas/genética
Ubiquitinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Benzimidazoles); 0 (Carcinogens); 0 (Cdkn1a protein, rat); 0 (Cyclin-Dependent Kinase Inhibitor p21); 0 (Rosaniline Dyes); 0 (UBD protein, human); 0 (Ubiquitins); 075T165X8M (Thioacetamide); 8U61G37Z20 (leucomalachite green); A01LX40298 (Methapyrilene); EC 2.7.- (Protein Kinases); EC 2.7.11.1 (CHEK1 protein, human); EC 2.7.11.1 (Checkpoint Kinase 1); EC 2.7.11.1 (Chek1 protein, rat); M2X04R2E2Y (Carbadox); OMP2H17F9E (oxfendazole)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:161126
[Lr] Data última revisão:
161126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151113
[St] Status:MEDLINE
[do] DOI:10.2131/jts.40.855


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[PMID]:25242409
[Au] Autor:Omura K; Uehara T; Morikawa Y; Hayashi H; Mitsumori K; Minami K; Kanki M; Yamada H; Ono A; Urushidani T
[Ad] Endereço:Drug Safety Research Laboratories, Astellas Pharma Inc.
[Ti] Título:Detection of initiating potential of non-genotoxic carcinogens in a two-stage hepatocarcinogenesis study in rats.
[So] Source:J Toxicol Sci;39(5):785-94, 2014.
[Is] ISSN:1880-3989
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:We previously reported a toxicogenomics-based prediction model for hepatocarcinogens in which the expression patterns of signature genes following repeated doses of either genotoxic or non genotoxic compounds were similar. Based on the results of our prediction model, we hypothesized that repeated doses of non-genotoxic carcinogens might have initiating potential. Here, we conducted a two stage hepatocarcinogenesis study in rats exposed to the initiating agent nitrosodiethylamine (DEN), and hepatotoxic compounds thioacetamide (TAA), methapyrilene (MP) and acetaminophen (APAP) for 1-2 weeks followed by the liver tumor promoter phenobarbital (PB). The duration of initial treatment was determined based on positive results from our prediction model. Combined treatment of 3 or 30 mg/kg of genotoxic DEN and PB induced marked increases in altered hepatocellular foci and a DEN dose-dependent increase in the number and area of glutathione S-transferase-placental form (GST-P)-positive foci. A low number of altered hepatocellular foci were also observed in rats treated with TAA at a dose of 45 mg/kg.MP at a dose of 100 mg/kg induced a very low number of foci, but APAP did not. Hierarchical clustering analysis using gene expression data revealed that 2-week treatment with TAA at a dose of 30 mg/kg and MP at 45 mg/kg induced specific expression of DNA damage-related genes, similar to 1-week treatment with DEN at a dose of 30 mg/kg. These results suggest that TAA and MP induce DNA damage, which partially supports our hypothesis. Although this study does not indicate whether tumor growth in response to these compounds can be assessed in this model, our results suggest that cumulative treatment with non genotoxic TAA might have initiating potential in the liver.
[Mh] Termos MeSH primário: Carcinoma Hepatocelular/induzido quimicamente
Neoplasias Hepáticas/induzido quimicamente
Metapirileno/toxicidade
Testes de Mutagenicidade/métodos
Tioacetamida/toxicidade
[Mh] Termos MeSH secundário: Acetaminofen/toxicidade
Animais
Carcinoma Hepatocelular/genética
Dano ao DNA/efeitos dos fármacos
Dano ao DNA/genética
Dietilnitrosamina/toxicidade
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Glutationa Transferase/metabolismo
Neoplasias Hepáticas/genética
Masculino
Estresse Oxidativo/genética
Fenobarbital/toxicidade
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
075T165X8M (Thioacetamide); 362O9ITL9D (Acetaminophen); 3IQ78TTX1A (Diethylnitrosamine); A01LX40298 (Methapyrilene); EC 2.5.1.18 (Glutathione Transferase); YQE403BP4D (Phenobarbital)
[Em] Mês de entrada:1504
[Cu] Atualização por classe:140922
[Lr] Data última revisão:
140922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140923
[St] Status:MEDLINE


  7 / 145 MEDLINE  
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[PMID]:23274394
[Au] Autor:Schug M; Stöber R; Heise T; Mielke H; Gundert-Remy U; Godoy P; Reif R; Blaszkewicz M; Ellinger-Ziegelbauer H; Ahr HJ; Selinski S; Günther G; Marchan R; Blaszkewicz M; Sachinidis A; Nüssler A; Oberemm A; Hengstler JG
[Ad] Endereço:Leibniz Research Centre for Working Environment and Human Factors at Dortmund TU, Dortmund, Germany.
[Ti] Título:Pharmacokinetics explain in vivo/in vitro discrepancies of carcinogen-induced gene expression alterations in rat liver and cultivated hepatocytes.
[So] Source:Arch Toxicol;87(2):337-45, 2013 Feb.
[Is] ISSN:1432-0738
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Cultivated hepatocytes represent a well-established in vitro system. However, the applicability of hepatocytes in toxicogenomics is still controversially discussed. Recently, an in vivo/in vitro discrepancy has been described, whereby the non-genotoxic rat liver carcinogen methapyrilene alters the expression of the metabolizing genes SULT1A1 and ABAT, as well as the DNA damage response gene GADD34 in vitro, but not in vivo. If the collagen sandwich cultures of hepatocytes really produce false-positive data, this would compromise its application in toxicogenomics. To revisit the putative in vivo/in vitro discrepancy, we first analyzed and modeled methapyrilene concentrations in the portal vein of rats. The relatively short half-life of 2.8 h implies a rapid decrease in orally administered methapyrilene in vivo below concentrations that can cause gene expression alterations. This corresponded to the time-dependent alteration levels of GADD34, ABAT and SULT1A1 RNA in the liver: RNA levels are altered 1, 6 and 12 h after methapyrilene administration, but return to control levels after 24 and 72 h. In contrast, methapyrilene concentrations in the culture medium supernatant of primary rat hepatocyte cultures decreased slowly. This explains why GADD34, ABAT and SULT1A1 were still deregulated after 24 h exposure in vitro, but not in vivo. It should also be considered that the earliest analyzed time point in the previous in vivo studies was 24 h after methapyrilene administration. In conclusion, previously observed in vitro/in vivo discrepancy can be explained by different pharmacokinetics present in vitro and in vivo. When the in vivo half-life is short, levels of some initially altered genes may have returned to control levels already 24 h after administration.
[Mh] Termos MeSH primário: Carcinógenos/farmacocinética
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Hepatócitos/efeitos dos fármacos
Fígado/efeitos dos fármacos
Metapirileno/farmacocinética
[Mh] Termos MeSH secundário: 4-Aminobutirato Transaminase/genética
Animais
Antígenos de Diferenciação/genética
Arilsulfotransferase/genética
Carcinógenos/toxicidade
Células Cultivadas
Meia-Vida
Hepatócitos/metabolismo
Fígado/metabolismo
Masculino
Metapirileno/toxicidade
Proteínas Proto-Oncogênicas/genética
RNA Mensageiro/metabolismo
Ratos
Ratos Wistar
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antigens, Differentiation); 0 (Carcinogens); 0 (Myd116 protein, rat); 0 (Proto-Oncogene Proteins); 0 (RNA, Messenger); A01LX40298 (Methapyrilene); EC 2.6.1.19 (4-Aminobutyrate Transaminase); EC 2.8.2.1 (Arylsulfotransferase); EC 2.8.2.1 (Sult1a1 protein, rat)
[Em] Mês de entrada:1307
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130101
[St] Status:MEDLINE
[do] DOI:10.1007/s00204-012-0999-8


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[PMID]:22414088
[Au] Autor:Heise T; Schug M; Storm D; Ellinger-Ziegelbauer H; Ahr HJ; Hellwig B; Rahnenfuhrer J; Ghallab A; Guenther G; Sisnaiske J; Reif R; Godoy P; Mielke H; Gundert-Remy U; Lampen A; Oberemm A; Hengstler JG
[Ad] Endereço:Federal Institute for Risk Assessment, Berlin, Germany.
[Ti] Título:In vitro - in vivo correlation of gene expression alterations induced by liver carcinogens.
[So] Source:Curr Med Chem;19(11):1721-30, 2012.
[Is] ISSN:1875-533X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Although cultivated hepatocytes are widely used in the studies of drug metabolism, their application in toxicogenomics is considered as problematic, because previous studies have reported only little overlap between chemically induced gene expression alterations in liver in vivo and in cultivated hepatocytes. Here, we identified 22 genes that were altered in livers of rats after oral administration of the liver carcinogens aflatoxin B1 (AB1), 2-nitrofluorene (2-NF), methapyrilene (MP) or piperonyl-butoxide (PBO). The functions of the 22 genes have been classified into two groups. Genes related to stress response, DNA repair or metabolism and genes associated with cell proliferation, respectively. Next, rat hepatocyte sandwich cultures were exposed to AB1, 2-NF, MP or PBO for 24h and expression of the above mentioned genes was determined by RT-qPCR. Significant correlations between the degree of gene expression alterations in vivo and in vitro were obtained for the stress, DNA repair and metabolism associated genes at concentrations covering a range from cytotoxic concentrations to non-toxic/in vivo relevant concentrations. In contrast to the stress associated genes, no significant in vivo/in vitro correlation was obtained for the genes associated with cell proliferation. To understand the reason of this discrepancy, we compared replacement proliferation in vivo and in vitro. While hepatocytes in vivo, killed after administration of hepatotoxic compounds, are rapidly replaced by proliferating surviving cells, in vitro no replacement proliferation as evidenced by BrdU incorporation was observed after washing out hepatotoxic concentrations of MP. In conclusion, there is a good correlation between gene expression alterations induced by liver carcinogens in vivo and in cultivated hepatocytes. However, it should be considered that cultivated primary hepatocytes do not show replacement proliferation explaining the in vivo/in vitro discrepancy concerning proliferation associated genes.
[Mh] Termos MeSH primário: Carcinógenos/farmacologia
Perfilação da Expressão Gênica
Regulação da Expressão Gênica/efeitos dos fármacos
Hepatócitos/efeitos dos fármacos
Hepatócitos/metabolismo
Fígado/efeitos dos fármacos
Fígado/metabolismo
[Mh] Termos MeSH secundário: Aflatoxina B1/administração & dosagem
Aflatoxina B1/farmacologia
Animais
Carcinógenos/administração & dosagem
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Dano ao DNA/efeitos dos fármacos
Dano ao DNA/genética
Reparo do DNA/efeitos dos fármacos
Reparo do DNA/genética
Regulação para Baixo/efeitos dos fármacos
Regulação para Baixo/genética
Fluorenos/administração & dosagem
Fluorenos/farmacologia
Regulação da Expressão Gênica/genética
Hepatócitos/citologia
Masculino
Metapirileno/administração & dosagem
Metapirileno/farmacologia
Butóxido de Piperonila/administração & dosagem
Butóxido de Piperonila/farmacologia
Ratos
Ratos Wistar
Estresse Fisiológico/efeitos dos fármacos
Estresse Fisiológico/genética
Regulação para Cima/efeitos dos fármacos
Regulação para Cima/genética
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carcinogens); 0 (Fluorenes); 191LL4U4GZ (2-nitrofluorene); 9N2N2Y55MH (Aflatoxin B1); A01LX40298 (Methapyrilene); LWK91TU9AH (Piperonyl Butoxide)
[Em] Mês de entrada:1210
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120315
[St] Status:MEDLINE


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[PMID]:22015589
[Au] Autor:Priestley CC; Regan S; Kevin Park B; Williams DP
[Ad] Endereço:Safety Assessment, AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. catherine.priestley@astrazeneca.com
[Ti] Título:The genotoxic potential of methapyrilene using the alkaline Comet assay in vitro and in vivo.
[So] Source:Toxicology;290(2-3):249-57, 2011 Dec 18.
[Is] ISSN:1879-3185
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:The genotoxicity of methapyrilne (MP) has been evaluated in a number of assays since it was found to be a rat hepatocarcinogen with subsequent withdrawal as an over-the-counter antihistamine. Whilst it has not been classified as a genotoxin, there are reports of positive findings from mammalian cell gene mutation and transformation assays. To investigate further the genotoxic potential of MP, the alkaline Comet assay was used to evaluate DNA damage both in primary hepatocytes in culture and in vivo in the rat. To confirm bioactivation was required to induce the hepatotoxic mechanism, aminobenzotriazole, a broad spectrum cytochrome P450 enzyme inhibitor was used as a pre-treatment. The levels of glutathione and glutathione disulfide were determined in both hepatocytes in culture and in the liver following in vivo exposure. MP showed significant increases in DNA damage in freshly isolated male rat hepatocyte suspensions that could be significantly reduced by pre-incubation of aminobenzotriazole (ABT). DNA damage showed a marked sex difference, with male hepatocytes being more susceptible, and showing a concurrent depletion of glutathione (GSH) compared with female hepatocytes. Modulation of the GSH levels by diethylmaleate and γ-glutamylcysteinylethyl ester, elevated and reduced the levels of DNA damage, respectively. In the in vivo Comet assay, there was no evidence of DNA damage following MP (150mg/kg p.o) treatment for three consecutive days, although histological and liver enzyme changes were seen. Total protein GSH content was elevated in MP-treated animals and superoxide dismutase levels were increased specifically in periportal regions. Taken together, these data support the potential for MP to induce oxidative stress. The differences in DNA damage detected by the Comet assay in vitro, and in rat liver in vivo, could be attributed to differences in metabolism and response to oxidant insult or the inability of the assay to discriminate damage in a small number of individual cells in the whole liver.
[Mh] Termos MeSH primário: Dano ao DNA/efeitos dos fármacos
Hepatócitos/efeitos dos fármacos
Antagonistas dos Receptores Histamínicos H1/toxicidade
Metapirileno/toxicidade
Estresse Oxidativo/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Ensaio Cometa
Feminino
Glutationa/efeitos dos fármacos
Glutationa/metabolismo
Hepatócitos/patologia
Fígado/efeitos dos fármacos
Fígado/patologia
Masculino
Testes de Mutagenicidade
Ratos
Ratos Wistar
Fatores Sexuais
Superóxido Dismutase/efeitos dos fármacos
Superóxido Dismutase/metabolismo
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Histamine H1 Antagonists); 0 (Triazoles); 1614-12-6 (1-aminobenzotriazole); A01LX40298 (Methapyrilene); EC 1.15.1.1 (Superoxide Dismutase); GAN16C9B8O (Glutathione)
[Em] Mês de entrada:1201
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:111022
[St] Status:MEDLINE
[do] DOI:10.1016/j.tox.2011.10.002


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[PMID]:21176868
[Au] Autor:Geenen S; Michopoulos F; Kenna JG; Kolaja KL; Westerhoff HV; Wilson I
[Ad] Endereço:Manchester Centre for Integrative Systems Biology and Doctoral Training Centre ISBML, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.
[Ti] Título:HPLC-MS/MS methods for the quantitative analysis of ophthalmic acid in rodent plasma and hepatic cell line culture medium.
[So] Source:J Pharm Biomed Anal;54(5):1128-35, 2011 Apr 05.
[Is] ISSN:1873-264X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Ophthalmic acid (OA), an endogenous tripeptide analogue of glutathione, has been suggested as a potential biomarker for paracetamol/acetaminophen hepatotoxicity. Here HPLC-MS/MS methods have been developed for the precise, sensitive and specific detection and quantification of OA in in vitro cell culture medium and plasma. For the cell culture medium the LLOQ was found to be 1 ng/ml, with less than 1% between sample carry over at all concentrations and precision below 15% for within day and below 9% for between day analyses. For rat plasma the presence of endogenous OA resulted in the LLOQ being 25 ng/ml (defined as the lowest concentration on the calibration curve where the base peak was less than 20% of the LLOQ). For the plasma assay the percentage carry over was less than 1% for all concentrations and within and between batch precision was below 21%. The methods were linear for both sample types from the LLOQ up to 5 µg/ml. The method was successfully applied to the determination of OA in samples obtained following the chronic administration of the rat hepatotoxin methapyrilene, where plasma OA concentrations were observed to show a weak negative correlation with those of established liver injury biomarkers such as aspartate aminotransferase (AST).
[Mh] Termos MeSH primário: Cromatografia Líquida de Alta Pressão/métodos
Meios de Cultura/análise
Células Epiteliais/metabolismo
Fígado/metabolismo
Oligopeptídeos/sangue
Espectrometria de Massas em Tandem/métodos
[Mh] Termos MeSH secundário: Animais
Biomarcadores/sangue
Linhagem Celular
Doença Hepática Induzida por Substâncias e Drogas/sangue
Doença Hepática Induzida por Substâncias e Drogas/etiologia
Células Epiteliais/citologia
Seres Humanos
Limite de Detecção
Fígado/citologia
Masculino
Metapirileno/toxicidade
Oligopeptídeos/análise
Ratos
Reprodutibilidade dos Testes
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Biomarkers); 0 (Culture Media); 0 (Oligopeptides); 3A60475Q1Q (ophthalmic acid); A01LX40298 (Methapyrilene)
[Em] Mês de entrada:1105
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:101224
[St] Status:MEDLINE
[do] DOI:10.1016/j.jpba.2010.11.038



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