Interactions of combined bile acids on hepatocyte viability: cytoprotection or synergism

Detalhes bibliográficos
Autor(a) principal: Rolo, Anabela P.
Data de Publicação: 2002
Outros Autores: Palmeira, Carlos M., Wallace, Kendall B.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10316/5420
https://doi.org/10.1016/S0378-4274(01)00464-7
Resumo: Cholestasis results from hepatocyte dysfunction due to the accumulation of bile acids in the cell, many of which are known to be cytotoxic. Recent evidence implicates competitive antagonism of key cytotoxic responses as the mechanism by which certain therapeutic bile acids might afford cytoprotection against cholestasis. In this work, we compare the relative cytotoxicity of bile acids in terms of dose- and time-dependence. To better elucidate the controversy related to the therapeutic use of ursodeoxycholate (UDCA) in cholestatic patients, we also evaluated the effects of bile acid combinations. Viability of Wistar rat hepatocytes in primary culture was measured by LDH leakage after 12 and 24 h exposure of cells to the various bile acids. All unconjugated bile acids caused a dose-dependent decrease in cell viability. The tauro- and glyco-conjugates of chenodeoxycholate (CDCA) and UDCA were all less toxic than the corresponding unconjugated form. Although relatively non-toxic, UDCA caused synergistic cell killing by lithocholate (LCA), CDCA, glyco-CDCA (GCDC) and tauro-CDCA (TCDC). Glycoursodeoxycholate decreased the toxicity of GCDC, but potentiated the toxicity of unconjugated CDCA and LCA. The tauro-conjugate of UDCA had no significant effect. These data suggest that at cholestatic concentrations, bile acid-induced cell death correlates with the degree of lipophilicity of individual bile acids. However, these results indicate that the reported improvement of biochemical parameters in cholestatic patients treated with UDCA is not due to a direct effect of UDCA on hepatocyte viability. Therefore, any therapeutic effect of UDCA must be secondary to some other process, such as altered membrane transport or nonparenchymal cell function.
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spelling Interactions of combined bile acids on hepatocyte viability: cytoprotection or synergismHepatocytesBile acidsUrsodeoxycholateMixturesCholestasisCholestasis results from hepatocyte dysfunction due to the accumulation of bile acids in the cell, many of which are known to be cytotoxic. Recent evidence implicates competitive antagonism of key cytotoxic responses as the mechanism by which certain therapeutic bile acids might afford cytoprotection against cholestasis. In this work, we compare the relative cytotoxicity of bile acids in terms of dose- and time-dependence. To better elucidate the controversy related to the therapeutic use of ursodeoxycholate (UDCA) in cholestatic patients, we also evaluated the effects of bile acid combinations. Viability of Wistar rat hepatocytes in primary culture was measured by LDH leakage after 12 and 24 h exposure of cells to the various bile acids. All unconjugated bile acids caused a dose-dependent decrease in cell viability. The tauro- and glyco-conjugates of chenodeoxycholate (CDCA) and UDCA were all less toxic than the corresponding unconjugated form. Although relatively non-toxic, UDCA caused synergistic cell killing by lithocholate (LCA), CDCA, glyco-CDCA (GCDC) and tauro-CDCA (TCDC). Glycoursodeoxycholate decreased the toxicity of GCDC, but potentiated the toxicity of unconjugated CDCA and LCA. The tauro-conjugate of UDCA had no significant effect. These data suggest that at cholestatic concentrations, bile acid-induced cell death correlates with the degree of lipophilicity of individual bile acids. However, these results indicate that the reported improvement of biochemical parameters in cholestatic patients treated with UDCA is not due to a direct effect of UDCA on hepatocyte viability. Therefore, any therapeutic effect of UDCA must be secondary to some other process, such as altered membrane transport or nonparenchymal cell function.http://www.sciencedirect.com/science/article/B6TCR-44J6KY8-2/1/fcf9ae6235aa2085c94caa05e81cf4242002info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleaplication/PDFhttp://hdl.handle.net/10316/5420http://hdl.handle.net/10316/5420https://doi.org/10.1016/S0378-4274(01)00464-7engToxicology Letters. 126:3 (2002) 197-203Rolo, Anabela P.Palmeira, Carlos M.Wallace, Kendall B.info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2021-10-07T10:32:21Zoai:estudogeral.uc.pt:10316/5420Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:55:29.299952Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Interactions of combined bile acids on hepatocyte viability: cytoprotection or synergism
title Interactions of combined bile acids on hepatocyte viability: cytoprotection or synergism
spellingShingle Interactions of combined bile acids on hepatocyte viability: cytoprotection or synergism
Rolo, Anabela P.
Hepatocytes
Bile acids
Ursodeoxycholate
Mixtures
Cholestasis
title_short Interactions of combined bile acids on hepatocyte viability: cytoprotection or synergism
title_full Interactions of combined bile acids on hepatocyte viability: cytoprotection or synergism
title_fullStr Interactions of combined bile acids on hepatocyte viability: cytoprotection or synergism
title_full_unstemmed Interactions of combined bile acids on hepatocyte viability: cytoprotection or synergism
title_sort Interactions of combined bile acids on hepatocyte viability: cytoprotection or synergism
author Rolo, Anabela P.
author_facet Rolo, Anabela P.
Palmeira, Carlos M.
Wallace, Kendall B.
author_role author
author2 Palmeira, Carlos M.
Wallace, Kendall B.
author2_role author
author
dc.contributor.author.fl_str_mv Rolo, Anabela P.
Palmeira, Carlos M.
Wallace, Kendall B.
dc.subject.por.fl_str_mv Hepatocytes
Bile acids
Ursodeoxycholate
Mixtures
Cholestasis
topic Hepatocytes
Bile acids
Ursodeoxycholate
Mixtures
Cholestasis
description Cholestasis results from hepatocyte dysfunction due to the accumulation of bile acids in the cell, many of which are known to be cytotoxic. Recent evidence implicates competitive antagonism of key cytotoxic responses as the mechanism by which certain therapeutic bile acids might afford cytoprotection against cholestasis. In this work, we compare the relative cytotoxicity of bile acids in terms of dose- and time-dependence. To better elucidate the controversy related to the therapeutic use of ursodeoxycholate (UDCA) in cholestatic patients, we also evaluated the effects of bile acid combinations. Viability of Wistar rat hepatocytes in primary culture was measured by LDH leakage after 12 and 24 h exposure of cells to the various bile acids. All unconjugated bile acids caused a dose-dependent decrease in cell viability. The tauro- and glyco-conjugates of chenodeoxycholate (CDCA) and UDCA were all less toxic than the corresponding unconjugated form. Although relatively non-toxic, UDCA caused synergistic cell killing by lithocholate (LCA), CDCA, glyco-CDCA (GCDC) and tauro-CDCA (TCDC). Glycoursodeoxycholate decreased the toxicity of GCDC, but potentiated the toxicity of unconjugated CDCA and LCA. The tauro-conjugate of UDCA had no significant effect. These data suggest that at cholestatic concentrations, bile acid-induced cell death correlates with the degree of lipophilicity of individual bile acids. However, these results indicate that the reported improvement of biochemical parameters in cholestatic patients treated with UDCA is not due to a direct effect of UDCA on hepatocyte viability. Therefore, any therapeutic effect of UDCA must be secondary to some other process, such as altered membrane transport or nonparenchymal cell function.
publishDate 2002
dc.date.none.fl_str_mv 2002
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dc.identifier.uri.fl_str_mv http://hdl.handle.net/10316/5420
http://hdl.handle.net/10316/5420
https://doi.org/10.1016/S0378-4274(01)00464-7
url http://hdl.handle.net/10316/5420
https://doi.org/10.1016/S0378-4274(01)00464-7
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Toxicology Letters. 126:3 (2002) 197-203
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