Cooperativity in the inhibition of oxidative phosphorylation by chlorophenoxyisobutyrate

The kinetics of inhibition of oxidative phosphorylation by the antihypercholes-terolaemic compound p-chlorophenoxyisobutyrate reveal cooperativity characteristic of allosteric interactions. Hill plots and Dixon plots give clear indication that the compound interferes with two distinct steps in the energy-transfer pathway. The values of interaction coefficients calculated from the Hill plots were two and four in the direction of ATP synthesis and one and two in the reverse direction. This could mean either that the pathways of synthesis and breakdown of ATP are different, or that if the pathways are the same, only half the inhibitor-binding sites function in the reverse direction

Effect of clofibrate on the adenosine triphosphatase activity of rat liver mitochondria

The antihypercholesterolemic drug clofibrate (ethyl-α-p-chlorophenoxyisobutyrate) stimulated the latent ATPase activity and “superstimulated” the uncoupler-induced ATPase activity of rat-liver mitochondria. Addition of clofibrate decreased the turbidity of mitochondrial suspensions and released considerable amount of mitochondrial protein into solution. In these properties it closely resembled detergents like Triton X-100 and deoxycholate. However, unlike the detergents, clofibrate required the presence of a permeant cation for its disruptive action. Also, it was without any such effect on sonic submitochondrial particles. The drug enhanced the uptake of both Mg2 and Cl− by mitochondria suggesting that osmotic swelling precedes lysis. Sonic submitochondrial particles prepared in the presence of clofibrate showed a greater yield and comparable ATPase activity

Nature of the inhibition by noradrenaline of induction by cortisol of hepatic tryptophan pyrrolase

Administration of noradrenaline inhibited the induction of hepatic trytophan pyrrolase by Cortisol but not by tryptophan. The selective inhibition of pyrrolase was specific to noradrenaline, whereas adrenaline and rat growth hormone also inhibited tyrosine aminotransferase. None of those three hormones had any effect on the incorporation of [32P]-orthophosphate into RNA, stimulated by cortisol. Other biogenic amines, polypeptide hormones and steroid analogues were not inhibitory to the induction of tryptophan pyrrolase by cortisol. The α-adrenergic agonist, phenylephrine, potentiated the noradrenaline inhibition whereas Image -threo-3,4-dihydroxyphenylserine, its precursor, together with pargyline had no effect on the induction process of pyrrolase. These results support the view that noradrenaline exerts its inhibitory action at the cell membrane via the α-receptor, and is not mediated directly by an intracellular mechanism