MECHANISM OF OXMETIDINE (SKANDF 92994) CYTO-TOXICITY IN ISOLATED RAT HEPATOCYTES

  • 1 January 1985
    • journal article
    • research article
    • Vol. 233  (3) , 741-746
Abstract
Oxmetidine is an H2-receptor antagonist that has efficacy in the treatment of peptic ulcers. Isolated rat hepatocytes exposed to oxmetidine (0.5 mM) rapidly lost viability as estimated by increased leakage of lactate dehydrogenase, incread formation of plasmsa membrane surface blebs and decreased intracellular K concentration [K+]. Oxmetidine caused a reduction in hepatocyte reduced glutathiione concentration that paralleled cell death; malondialdehyde formation was not observed. Hepatocyte respiration (O2 consumption) and intracellular ATP concentration were decreased markedly by oxmetidine in a concentration-related fashion. Oxmetidine (50 .mu.M) blocked pyruvate/malate-supported state 3 (ADP-stimulated) respiration, caused a decrease in the ADP:O ratio and a loss of respiratory control in isolated rat liver mitochondria. Oxmetidine did not blocked succinate-supported ADP-stimulated O2 consumption in isolated rat liver mitochondria. Oxmetidine was cytotoxic to isolated rat hepatocytes in suspension and the mechanism of oxmetidine-induced hepatoycte injury may be related to sustained inhibition of mitochondrial oxidative phosphorylation leading to decreased cellular ATP content and cell death. Although the exact site of action of oxmetidine within the mitochondrion has not been completely elucidated, it appears to reside in the inner mitochondria membrane electron transport chain before ubiquinone oxidoreductase.

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