Glycochenodeoxycholate-induced lethal hepatocellular injury in rat hepatocytes. Role of ATP depletion and cytosolic free calcium.

Spivey, James R.; Bronk, Steven F.; Gores, Gregory J.

doi:10.1172/jci116546

Cited by 239 publications

(172 citation statements)

References 51 publications

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“…The fact that conjugation with either glycine or taurine decreased cytotoxicity of CDCA agrees with the observations made by others (Scholmerich et al, 1984). In contrast, Spivey et al (1993) reported that at a concentration of 250 mM, GCDC was more toxic than either CDCA or TCDC. Significant differences in the experimental procedure may explain the discrepancy.…”

Section: Resultssupporting

confidence: 90%

“…Significant differences in the experimental procedure may explain the discrepancy. For instance, Spivey et al (1993) worked with hepatocytes after only 2 h in culture.…”

Section: Resultsmentioning

confidence: 99%

“…Although some studies reported bile acids effects on cell viability (Delzenne et al, 1992;Spivey et al, 1993;Hillaire et al, 1995), no systematic study has been carried out. With growing debate regarding the effectiveness of UDCA and conjugates in patients with cholestasis, several important questions are raised, one of which is whether the observed effects of UDCA in vivo are related to a direct effect at the hepatocyte level.…”

Section: Introductionmentioning

confidence: 99%

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

2002

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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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Section: Resultssupporting

confidence: 90%

“…Significant differences in the experimental procedure may explain the discrepancy. For instance, Spivey et al (1993) worked with hepatocytes after only 2 h in culture.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

2002

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“…Spivey et al 2 concluded that the bile salt-induced liver toxicity was due to mitochondrial disfunction, resulting in depleted ATP levels and sustained influx of Ca 2+ leading to hepatocyte necrosis.…”

Section: Discussionmentioning

confidence: 99%

Níveis elevados de transaminases em um caso de coledocolitíase: a importância do reconhecimento deste padrão

Ferri¹,

Silva²,

Filho³

et al. 2017

Rev. Med. (São Paulo)

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Case report of a 34-year-old healthy woman diagnosed with symptomatic choledocholithiasis associated with elevated results of transaminases without hepatic disease. High levels of these enzymes can occur in choledocholithiasis cases without further causes of liver injury. Clinicians must be aware of this phenomenon, avoiding unnecessary investigation and its consequences.Keywords: Choledocholithiasis; Transaminases; Women. RESUMO:Relato de caso de uma mulher hígida de 34 anos de idade diagnosticada com coledocolitíase sintomática associada a elevados níveis de transaminases, sem doença hepática. Altos valores destas enzimas podem ocorrer na coledocolitíase sem outra causa de lesão hepática concomitante. Os médicos devem estar atentos a este fenômeno, a fim de se evitar investigação desnecessária e suas consequências.

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“…that this may be due to the ATP-lowering effect of 2-DG (Foufelle et al 1992). Indeed, lowering of cytosolic ATP/ADP ratios increases cytosolic Ca 2C by inhibiting ATP-dependent pumping into both the extracellular space and intracellular stores (Haworth et al 1987, Spivey et al 1993, Bright et al 1995. The resultant elevation of cytosolic free Ca 2C may then be sufficient to evoke ChREBP nuclear translocation (Noordeen et al 2012) and thus activate the transcription of target genes.…”

Section: Regulation Of Chrebp Activation By Glucosementioning

confidence: 99%

Roles of Ca2+ ions in the control of ChREBP nuclear translocation

Leclerc

Rutter²,

Meur³

et al. 2012

Journal of Endocrinology

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Carbohydrate-responsive element binding protein (ChREBP (MLXIPL)) is emerging as an important mediator of glucotoxity both in the liver and in the pancreatic b-cells. Although the regulation of its nuclear translocation and transcriptional activation by glucose has been the subject of intensive research, it is still not fully understood. We have recently uncovered a novel mechanism in the excitable pancreatic b-cell where ChREBP interacts with sorcin, a penta-EF-hand Ca -sorcin element of ChREBP activation also exists in non-excitable cells is discussed.

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Glycochenodeoxycholate-induced lethal hepatocellular injury in rat hepatocytes. Role of ATP depletion and cytosolic free calcium.

Cited by 239 publications

References 51 publications

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

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

Níveis elevados de transaminases em um caso de coledocolitíase: a importância do reconhecimento deste padrão

Roles of Ca2+ ions in the control of ChREBP nuclear translocation

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