The inhibition of oxidative phosphorylation.

Loomis & Lipmann (1948) showed that low concentrations of 2:4-dinitrophenol (DNP) reversibly uncouple the phosphorylation associated with the oxidation of glutamate. This supported the hypothesis that agents such as DNP, which prevent the use of the energy provided by respiration and glycolysis, do so by inhibiting the formation of highenergy phosphate bonds (Lardy & Elvehjem, 1945; McElroy, 1947). The acceleration of respiration and glycolysis of intact cells by low concentrations of DNP (see Peiss & Field, 1948, for references) might thus be explained in terms of an increased availability of orthophosphate and of adeninenucleotide acceptors which normally limit the rate of carbohydrate breakdown (cf. Meyerhof & Geliazkowa, 1947). Johnson (1941) has suggested that the Pasteur effect is a consequence of the greater efficiency of aerobic phosphorylation compared with that associated with glycolysis, a view which is consistent with the inhibition of the Pasteur effect by DNP (Dodds & Greville, 1934). Lynen (1941) has indeed shown that respiration reduces the amount of orthophosphate available for yeast fermentation. Some interest is therefore attached to the action of other compounds known to accelerate respiration and/or aerobic glycolysis on oxidative phosphorylation. For example, phenosafranine in suitable concentration will increase the aerobic glycolysis of ratbrain and tumour slices without affecting' the respiration. Dyestuffs such as thionine accelerate the respiration of many tissues without influencing the aerobic glycolysis (Dickens, 1936a, b), while 4:6-dinitro-o-cresol increases both respiration and aerobic glycolysis (Dickens, 1939). We have, therefore, investigated the action of a number of known inhibitors of the Pasteur effect, as well as some metabolites of DNP, on the coupling between oxidation and phosphorylation. Two hormones, thyroxine and insulin, which we thought might possibly influence oxidative phosphorylation, have also been tested. The enzyme systems that we have used in this investigation were those contained in cyclophorase preparations and in mitochondria of rat and rabbit liver and kidney. Hogeboom, Schneider & Pallade (1948) and Kennedy & Lehninger (1948, 1949) have