The Actions of Carbenoxolone on Gluconeogenesis and Oxygen Consumption in Livers of Fasted Rats Using Lactate as Exogenous Substrate

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 if carbenoxolone affects gluconeogenesis in the rat liver. Male Wistar rats, weighing 180 to 220 g, fed with a standard laboratory diet were utilized. But in this case, the rats were starved for 24 hours before the surgical removal of the liver. The isolated liver was perfused in the non-recirculating system. The perfusion fluid was Krebs/Henseleit-bicarbonate buffer (pH 7.4), saturated with a mixture of O2 and CO2 (95:5) by means of a membrane oxygenator and simultaneously heated to 37C. In livers of 24-hours fasted rats, carbenoxolone inhibited gluconeogenesis from lactate, as well as inhibited oxygen consumption, which is an expected combination of phenomena for decreased mitochondrial ATP formation.