Mechanism of oxmetidine (SK&F 92994) cytotoxicity in isolated rat hepatocytes.
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, increased formation of plasma membrane surface blebs and decreased intracellular potassium concentration [K+]. Oxmetidine caused a reduction in hepatocyte reduced glutathione 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 microM) blocked pyruvate/malate-supported state 3 (ADP-stimulated) respiration, caused a decrease in the ADP:0 ratio and a loss of respiratory control in isolated rat liver mitochondria. In contrast, oxmetidine did not block succinate-supported ADP-stimulated O2 consumption in isolated rat liver mitochondria. These data demonstrate that: 1) oxmetidine was cytotoxic to isolated rat hepatocytes in suspension and 2) the mechanism of oxmetidine-induced hepatocyte 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 mitochondrial membrane electron transport chain before ubiquinone oxidoreductase.
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D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D005978:Glutathione / Q000032:analysis; D006635:Histamine H2 Antagonists / Q000633:toxicity*; D007093:Imidazoles / Q000633:toxicity*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D006635:Histamine H2 Antagonists; D007093:Imidazoles; D000255:Adenosine Triphosphate; D005978:Glutathione; C027703:oxmetidine