Effects of salicylate and other benzoates on oxidative enzymes of the tricarboxylic acid cycle in rat tissue homogenates

Salicylate and enzymes

“…The latter response suggested that respiratory enzymes, less sensitive to the drug than the oxidative phosphorylation reactions, were being inhibited by the higher salicylate concentrations. Studies on the oxidation of intermediary metabolites by tissue homogenates (Kaplan, Kennedy & Davis, 1954) and the transfer of radioactivity from labelled metabolites in mitochondria (Bryant, Smith & Hines, 1963) indicated that 5-7 mM salicylate inhibits dehydrogenase enzymes in the tricarboxylic acid cycle. Later work (Baker, Lee & others, 1960;Bargoni, 1964;Hines & Smith, 1964;Grisolia, Mendelson & Diederich, 1969) showed that the drug inhibits a wide variety of pyridine nucleotidedependent dehydrogenases.…”

Kinetic Model of Mitochondrial Krebs Cycle: Unraveling the Mechanism of Salicylate Hepatotoxic Effects

“…To estimate the values of the unknown inhibition constants for salicylate for KGDH and SDH we have fitted the new model to experimentally measured dependences on oxygen consumption. Figure 4 demonstrates that experimental data from [5] (symbols) and theoretical curves corresponding to our model of the Krebs cycle oxidizing α-ketoglutarate closely coincide. Values of the inhibition constants are listed in Table II.…”

“…Using either the first or the second set of values for the parameters in the system of differential equations (1), and calculating the steady-state values of the intermediate concentrations and fluxes, we have estimated the influence of uncoupling on the functioning of the Krebs cycle. (C) α-ketoglutarate dehydrogenase and succinate dehydrogenase can be inhibited by salicylates [5]. Since the mechanisms of interaction between salicylates and these enzymes are unknown, we have assumed that both α-ketoglutarate dehydrogenase and succinate dehydrogenase are inhibited by salicylates in an uncompetitive manner [20].…”

“…To estimate the values of the inhibition constants of the two enzymes with respect to salicylates, experimental data [5] have been used where the following experiments have been performed: a suspension of mitochondria respiring on α-ketoglutarate has been incubated in media with and without salicylate. Then, time series of oxygen concentration consumed by these mitochondria have been measured.…”

“…It is known that, during utilization in the liver, salicylates can inhibit β-oxidation of fatty acids [3], decrease the pool of coenzyme A (CoA) [4], inhibit succinate dehydrogenase and α-ketoglutarate dehydrogenase [5], and increase the permeability of the inner mitochondrial membrane, thereby decreasing the proton motive force [6,7]. One of the reasons for liver injury during aspirin therapy is the disturbance of the hepatocyte energy metabolism, particularly in the Krebs cycle.…”