Acute Oxygen Supplementation Restores Markers of Hepatocyte Energy Status and Hypoxia in Cirrhotic Rats

The oxygen limitation hypothesis states that hepatocyte hypoxia is the mechanism determining metabolic restriction in the cirrhotic liver. Therefore we studied markers of hepatocyte energy state and cellular hypoxia in livers of normal and cirrhotic rats before and after oxygen supplementation. Rats...

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Published in:The Journal of pharmacology and experimental therapeutics 2000-05, Vol.293 (2), p.641
Main Authors: Harvey, P J, Gready, J E, Yin, Z, Le Couteur, D G, McLean, A J
Format: Article
Language:English
Subjects:
Animals
Biomarkers
Blood Gas Analysis
Carbon Tetrachloride Poisoning - enzymology
Carbon Tetrachloride Poisoning - metabolism
Energy Metabolism - drug effects
Hypoxia - metabolism
Lactic Acid - metabolism
Liver - drug effects
Liver - enzymology
Liver - metabolism
Liver Cirrhosis, Experimental - chemically induced
Liver Cirrhosis, Experimental - enzymology
Liver Cirrhosis, Experimental - metabolism
Magnetic Resonance Spectroscopy
Male
Oxygen - pharmacology
Perchlorates - metabolism
Phosphorylation
Pyruvic Acid - metabolism
Rats
Rats, Wistar
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Summary:The oxygen limitation hypothesis states that hepatocyte hypoxia is the mechanism determining metabolic restriction in the cirrhotic liver. Therefore we studied markers of hepatocyte energy state and cellular hypoxia in livers of normal and cirrhotic rats before and after oxygen supplementation. Rats with carbon tetrachloride-induced cirrhosis and procedural control rats were exposed to either room air or a hyperoxic gas mixture for 1 h immediately before freeze clamping and perchloric acid extraction of liver tissue. Extracts were assessed by 31 P NMR and enzymatic assays. Livers from cirrhotic rats breathing room air showed a reduced ratio of ATP/ADP, an increased ratio of inorganic phosphate/ATP, and a trend toward an increased ratio of lactate/pyruvate compared with procedural control livers (ATP/ADP 1.73 ± 0.35 versus 2.68 ± 0.61, P < .05; P i /ATP 2.74 ± 0.48 versus 1.56 ± 0.26, P < .05; lactate/pyruvate 29.3 ± 6.4 versus 22.5 ± 7.4, P = .18). After supplementation with oxygen for 1 h, these ratios in cirrhotic livers approached control values. A variety of other metabolic markers affected by cirrhosis showed variable trends toward normal in response to oxygen supplementation, whereas minor trends toward an increase in ATP levels in control animals suggest the possibility of marginal oxygen limitation in normal livers. The data are consistent with the hypothesis that hepatocytes in cirrhotic livers have normal metabolic capacity but are constrained by a deficit in oxygen supply. Interventions aimed at increasing oxygen supply to the liver may have both short- and long-term therapeutic value in the management of cirrhosis.
ISSN:0022-3565
1521-0103