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Abstract

Mechanism of inhibition of rat liver mitochondrial respiration by oxmetidine, an H2-receptor antagonist.

G D Hoke, H Y Cheng, C K Mirabelli and G F Rush
Journal of Pharmacology and Experimental Therapeutics March 1990, 252 (3) 908-914;
G D Hoke
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H Y Cheng
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C K Mirabelli
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G F Rush
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Abstract

Suspensions of rat liver hepatocytes exposed to oxmetidine rapidly lose viability, an event preceded by a marked and rapid inhibition of cell respiration and depletion of ATP. In isolated rat liver mitochondria (RLM), oxmetidine inhibits pyruvate/malate- but not succinate-supported, ADP-stimulated oxygen consumption (state 3). The purpose of this investigation was to determine the exact molecular site of oxmetidine-induced inhibition of RLM electron transport. Oxmetidine did not significantly inhibit succinate-supported, ADP-stimulated state 3 oxygen consumption in isolated RLM at concentrations up to 0.5 mM. In contrast, oxmetidine significantly inhibited beta-hydroxybutyrate- or isocitrate-supported mitochondrial state 3 oxygen consumption at concentrations above 10 microM and 25 microM, respectively. In RLM electron transport particles (ETP), oxmetidine inhibited NADH-oxidase and NADH-CoQ reductase activity (IC50 of 3.4 microM and 2.6 microM, respectively). However, oxmetidine did not significantly affect NADH-Fe3(CN)6 reductase activity (at concentrations up to 200 microM). SK&F 92058, a thiourea analog of oxmetidine approximately 24-fold less toxic to hepatocytes, produced a similar pattern of inhibition of respiration, although far less potent (IC50 of 0.8 mM and 0.6 mM for NADH-oxidase and NADH-CoQ reductase, respectively). SK&F 92058 did not significantly inhibit NADH-Fe3(CN)6 reductase activity at concentrations up to 3.0 mM. Studies with [14C]oxmetidine failed to show any specific, saturable binding to rat liver ETP.(ABSTRACT TRUNCATED AT 250 WORDS)

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Journal of Pharmacology and Experimental Therapeutics
Vol. 252, Issue 3
1 Mar 1990
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Abstract

Mechanism of inhibition of rat liver mitochondrial respiration by oxmetidine, an H2-receptor antagonist.

G D Hoke, H Y Cheng, C K Mirabelli and G F Rush
Journal of Pharmacology and Experimental Therapeutics March 1, 1990, 252 (3) 908-914;

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Abstract

Mechanism of inhibition of rat liver mitochondrial respiration by oxmetidine, an H2-receptor antagonist.

G D Hoke, H Y Cheng, C K Mirabelli and G F Rush
Journal of Pharmacology and Experimental Therapeutics March 1, 1990, 252 (3) 908-914;
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