Mode of Action of Hypoglycemic Agents

Abstract

Abstract Quinaldic acid and 5-methoxy indole-2-carboxylic acid inhibited the oxidation of pyruvate, α-ketoglutarate, glutamate, and citrate but not of β-hydroxybutyrate or succinate in rat liver mitochondria. The inhibition of glutamate and citrate metabolism resulted primarily from inhibition of the further oxidation of α-ketoglutarate. Isolated liver mitochondria accumulated these inhibitors to concentrations 30-fold in excess of those found in the suspending medium. Octanoate or 2,4-dinitrophenol reduced this accumulation and also reversed the inhibition of pyruvate oxidation. Kidney mitochondria did not accumulate these aromatic monocarboxylic acid inhibitors to nearly the same extent as liver mitochondria; neither compound inhibited kidney mitochondrial oxidations. The site of inhibition was lipoyl dehydrogenase. Concentrations of the inhibitors which could be accumulated by isolated mitochondria significantly inhibited the enzyme isolated from rat liver mitochondria. The specificity of various indole derivatives indicated that different structural requirements were necessary for accumulation by mitochondria, inhibition of isolated lipoyl dehydrogenase, and, finally, inhibition of α-keto acid oxidation.