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PMID: 8325981 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The Journal of clinical investigation ·Vol. 92 ·No. 1 ·1993-07-00 ·Pages 17-24

Spivey JR, Bronk SF, Gores GJ

Abstract

Chenodeoxycholate is toxic to hepatocytes, and accumulation of chenodeoxycholate in the liver during cholestasis may potentiate hepatocellular injury. However, the mechanism of hepatocellular injury by chenodeoxycholate remains obscure. Our aim was to determine the mechanism of cytotoxicity by chenodeoxycholate in rat hepatocytes. At a concentration of 250 microM, glycochenodeoxycholate was more toxic than either chenodeoxycholate or taurochenodeoxycholate. Cellular ATP was 86% depleted within 30 min after addition of glycochenodeoxycholate. Fructose, a glycolytic substrate, maintained ATP concentrations at 50% of the initial value and protected against glycochenodeoxycholate cytotoxicity. ATP depletion in the absence of a glycolytic substrate suggested impairment of mitochondrial function. Indeed, glycochenodeoxycholate inhibited state 3 respiration in digitonin-permeabilized cells in a dose-dependent manner. After ATP depletion, a sustained rise in cytosolic free calcium (Cai2+) was observed. Removal of extracellular Ca2+ abolished the rise in Cai2+, decreased cellular proteolysis, and protected against cell killing by glycochenodeoxycholate. The results suggest that glycochenodeoxycholate cytotoxicity results from ATP depletion followed by a subsequent rise in Cai2+. The rise in Cai2+ leads to an increase in calcium-dependent degradative proteolysis and, ultimately, cell death. We conclude that glycochenodeoxycholate causes a bioenergetic form of lethal cell injury dependent on ATP depletion analogous to the lethal cell injury of anoxia.

MeSH Terms
Adenosine Triphosphate/metabolism Animals Calcium/metabolism Cell Survival/drug effects Cells, Cultured Chemical and Drug Induced Liver Injury Cholestasis/physiopathology Cytosol/metabolism Glycochenodeoxycholic Acid/toxicity Hydrogen-Ion Concentration In Vitro Techniques Intracellular Membranes/drug effects Male Membrane Potentials/drug effects Mitochondria, Liver/drug effects Proteins/metabolism Rats Rats, Sprague-Dawley
Chemicals
Proteins Glycochenodeoxycholic Acid Adenosine Triphosphate Calcium
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Spivey J R
Department of Internal Medicine, Mayo Medical School, Rochester, Minnesota 55905.
Bronk S F
Gores G J
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI116546
Published
1993-07-00
Pages
17-24
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC293519
Subset
IM
Grants
NIDDK NIH HHS · DK-45331 · United States
External Links
PubMed source DOI: 10.1172/JCI116546 PMC Full Text View journal details
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