[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
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[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
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[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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