The inhibition of the mitochondrial NADH oxidase by alprenolol and the protective effect of cytochrome P-450.

Abstract

Abstract: The presence of the β‐receptor blocking drug alprenolol at a low concentration was found to inhibit markedly the uptake of oxygen catalyzed by liver or heart mitochondria in the presence of β‐hydroxybutyrate but not in the presence of succinate. The same was true for the endogenous oxygen uptake by heart slices but not by liver slices or isolated liver cells. In the latter two systems, the rate of oxygen uptake was inhibited only at considerably higher concentrations of the drug. However, in the presence of SKF 525‐A — which prevents the binding of alprenolol to cytochrome P‐450 — liver slices and isolated liver cells were as sensitive as isolated mitochondria to the inhibitory effect on oxygen uptake by alprenolol. Furthermore, liver homogenates or combinations of the liver mitochondrial and microsomal fractions, in the presence or absence of NADPH, exhibited almost the same sensitivity towards the inhibitory effect of alprenolol on oxygen consumption as the mitochondrial fraction. Thus, the results indicate that alprenolol is a rather potent inhibitor of NADH‐linked mitochondrial oxidations, its site of action being localized between NADH and ubiquinone. In the intact liver cell, however, the mitochondria seem to be largely protected from this toxic effect by trapping of the drug by cytochrome P‐450. This may in turn be of importance for decreasing the hepatic toxicity of the high concentrations of alprenolol resulting from the efficient liver extraction after oral administration of this drug.