RT Journal Article
SR Electronic
T1 Acute Oxygen Supplementation Restores Markers of Hepatocyte Energy Status and Hypoxia in Cirrhotic Rats
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 641
OP 645
VO 293
IS 2
A1 Peta J. Harvey
A1 Jill E. Gready
A1 Zhanli Yin
A1 David G. Le Couteur
A1 Allan J. McLean
YR 2000
UL http://jpet.aspetjournals.org/content/293/2/641.abstract
AB 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 by31P 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; Pi/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. The American Society for Pharmacology and Experimental Therapeutics