Mechanism of inhibition of rat liver mitochondrial respiration by oxmetidine, an H2-receptor antagonist.
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)
Hoke
G D
GD
Department of Molecular Pharmacology, SmithKline and French Laboratories, King of Prussia, Pennsylvania.
Cheng
H Y
HY
Mirabelli
C K
CK
Rush
G F
GF
D000818:Animals; D004579:Electron Transport / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000378:metabolism / Q000633:toxicity*; D007093:Imidazoles / Q000378:metabolism / Q000633:toxicity*; D008785:Metiamide / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats
D006635:Histamine H2 Antagonists; D007093:Imidazoles; D008785:Metiamide; C027703:oxmetidine