THE EFFECTS OF CARBENOXOLONE ON ENERGY METABOLISM OF RAT LIVER MITOCHONDRIA

Abstract

Carbenoxolone is a derivative of glycyrrhetinic acid, the active principle of licorice (Glycyrrhiza glabra), a medicinal root. The pharmacological properties attributed to carbenoxolone are related to its inhibitory actions on the 11β-hydroxysteroid dehydrogenase and gap junction channels. Recent studies have shown that carbenoxolone also induces swelling and membrane potential collapse in mitochondria. These effects were related to hydrogen peroxide generation and mitochondrial permeability transition (MPT) induction, indicating possible toxicological actions of carbenoxolone at the mitochondrial level, which could trigger the apoptotic pathway. The data of these previous reports are pointing, thus, in the direction of a possible action of carbenoxolone on the bioenergetic functions of mitochondria, which could in turn cause toxic metabolic changes in the liver. For this reason, the present work was planned to investigate the action of carbenoxolone on respiratory and ATPase activity of isolated rat liver mitochondria. Male Wistar rats, weighing 180 to 220 g, fed with a standard laboratory diet were utilized. Mitochondrial respiration was measured polarographically. The mitochondrial ATPase activity was measured in intact (coupled and uncoupled) and in freeze-thawing disrupted mitochondria. In isolated mitochondria, carbenoxolone increased state IV respiration and respiration dependent solely on succinate and β-hydroxybutyrate oxidation. However, it decreased state III respiration and diminished the respiratory control ratio. Carbenoxolone stimulated the ATPase activity of intact mitochondria and inhibited the ATPase activity of uncoupled mitochondria. The ATPase activity of freeze-thawing disrupted mitochondria was not altered. Carbenoxolone impairs energy metabolism probably acting as an uncoupler of oxidative hosphorylation.