Disease relevance of Glycochenodeoxycholate

• We conclude that glycochenodeoxycholate causes a bioenergetic form of lethal cell injury dependent on ATP depletion analogous to the lethal cell injury of anoxia [1].
• Immunoblotting of GCDC-treated McNtcp.24 hepatoma cells demonstrated cleavage of poly(ADP-ribose) polymerase and lamin B1 to fragments that indicate activation of effector caspases [2].
• Addition of ursodeoxycholate, which by itself proved to be of little toxicity, significantly reduced the hepatotoxic effects of glycochenodeoxycholate: 72% +/- 6% of the cells survived treatment with 500 mumol/L glycochenodeoxycholate alone, but addition of 100 mumol/L ursodeoxycholate increased the survival rate to 87% +/- 4% (p less than 0.05) [3].
• The accumulation of glycochenodeoxycholate (GCDC) induced hepatocyte apoptosis in cholestasis [4].
• Exposure of Salmonella enterica to sodium cholate, sodium deoxycholate, sodium chenodeoxycholate, sodium glychocholate, sodium taurocholate, or sodium glycochenodeoxycholate induces the SOS response, indicating that the DNA-damaging activity of bile resides in bile salts [5].

High impact information on Glycochenodeoxycholate

• After GCDC treatment, immunoprecipitation experiments demonstrated Fas oligomerization, and confocal microscopy demonstrated DeltaFADD-GFP (Fas-associated death domain-green fluorescent protein, aggregation in the absence of detectable Fas ligand mRNA [2].
• Transfection with CrmA, an inhibitor of caspase 8, prevented GCDC-induced cathepsin B activation and apoptosis [2].
• Cholestatic liver injury appears to result from the induction of hepatocyte apoptosis by toxic bile salts such as glycochenodeoxycholate (GCDC) [2].
• RESULTS: Within 1 minute, the proapoptotic bile salts taurolithocholate-3-sulfate and glycochenodeoxycholate induced oxidative stress and EGF receptor (EGF-R) tyrosine phosphorylation followed by rapid c-Jun-N-terminal kinase (JNK) activation [6].
• In contrast, both GCDC and TCDC treatment resulted in Fas aggregation and recruitment of a dominant-negative FADD green fluorescent protein (GFP) and C360S procaspase 8-GFP to the plasma membrane [7].

Chemical compound and disease context of Glycochenodeoxycholate

• Incubation of glycocholate or glycochenodeoxycholate for 60 h with Eubacterium tortuosum from one patient or Escherichia coli from another produced the types of bile acids found in the duodenum of those patients [8].

Biological context of Glycochenodeoxycholate

• Cell viability was also increased in hepatocytes from BDL rats vs. controls after treatment with GCDC [9].
• The GCDC-induced downregulation of gp130 protein expression was insensitive to inhibition of proteasomal or lysosomal protein degradation but turned out to be sensitive to inhibition of caspase-3 or caspase-8 activity [10].
• Glycochenodeoxycholate plays a carcinogenic role in immortalized mouse cholangiocytes via oxidative DNA damage [11].
• Ursodeoxycholate (UDCA) inhibits the mitochondrial membrane permeability transition induced by glycochenodeoxycholate: a mechanism of UDCA cytoprotection [12].
• In summary, during treatment of hepatocytes with GCDC, (1) apoptosis is associated with lipid peroxidation, and (2) the antioxidant lazaroid U83836E inhibits both lipid peroxidation and apoptosis [13].

Anatomical context of Glycochenodeoxycholate

• Glycochenodeoxycholate-induced lethal hepatocellular injury in rat hepatocytes. Role of ATP depletion and cytosolic free calcium [1].
• RESULTS: After addition of glycochenodeoxycholate (GCDC), the magnitude of the MPT was reduced in mitochondria from BDL rats vs. controls [9].
• Despite recruitment of procaspase 8 to the plasma membrane by both bile acids, only GCDC resulted in increases of caspase 8 activity and Bid-GFP mitochondrial translocation [7].
• Taurocholate damaged the mucosa only at pH 1, whereas glycochenodeoxycholate caused injury at pH 1 and 3 [14].
• Solutions of taurocholate or of glycochenodeoxycholate, with or without added Questran, were instilled into the stomachs of fasted mice at pH 1, 3, 5, and 7 [14].

Associations of Glycochenodeoxycholate with other chemical compounds

• RESULTS: GCDC, but not TCDC, resulted in cytochrome c release demonstrating that TCDC blocked apoptosis upstream of mitochondria [7].
• Feeding BDL rats a fatty acid-deficient diet prevented the increase in mitochondrial cardiolipin content; mitochondria and hepatocytes from these rats were susceptible to the MPT and hepatocellular death by GCDC [9].
• It was shown that hydrophobic bile acids such as glycochenodeoxycholate (GCDC) inhibited IL-6-induced tyrosine phosphorylation of signal transducer and activator of transcription (STAT) 3 in hepatocytes and in perfused rat liver [10].
• Fructose inhibited glycochenodeoxycholate (GCDC)-induced apoptosis in a concentration-dependent manner with a maximum inhibition of 72% +/- 10% at 10 mmol/L [15].
• This inhibition was accompanied by GCDC-mediated downregulation of glycoprotein (gp) 130 expression, whereas gp130 and suppressor of cytokine signaling 3 messenger RNA and gp80 protein levels remained unaffected [10].

Gene context of Glycochenodeoxycholate

• GCDCA stimulated phosphorylation of both cFLIP isoforms, which was associated with decreased binding to GST-FADD [16].
• The bile acid glycochenodeoxycholate induces trail-receptor 2/DR5 expression and apoptosis [17].
• GCDC time-dependently induced caspase 3 (3.4-fold)- and caspase 9 (1.4-fold)-mediated apoptosis of cholangiocytes, but this was inhibited by lecithins and TUDC [18].
• We studied the effect of hepatocyte growth factor on glycochenodeoxycholate-induced apoptosis to determine whether hepatocyte growth factor protects hepatocytes against bile acid-induced apoptosis and whether the protective effect is mediated via phosphoinositide 3-kinase and/or mitogen-activated protein kinase pathways [19].
• Chelerythrine and Gö-6976 reduced, whereas PMA enhanced, cathepsin B activity during treatment of hepatocytes with GCDC, demonstrating coupling of PKC activity to the protease effector mechanisms of apoptosis [20].

Analytical, diagnostic and therapeutic context of Glycochenodeoxycholate

• Hepatocytes were obtained by collagenase perfusion of healthy human liver tissue and were treated with glycochenodeoxycholate for 24 hr 1 day after plating [3].
• Under the non-equilibrium conditions of gel chromatography no binding of glycochenodeoxycholate or glycocholate to any of the lymph proteins was observed [21].
• Hepatocellular apoptosis in the BDL group was obviously decreased as compared with normal control group after addition of 100 mumol/L GCDC to the cells for 24 h [22].

References