Metabolic effects of carbenoxolone in rat liver

✍ Scribed by Leandro Silva Pivato; Rodrigo Polimeni Constantin; Emy L. Ishii-Iwamoto; Ana Maria Kelmer-Bracht; Nair Seiko Yamamoto; Jorgete Constantin; Adelar Bracht

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 319 KB
• Volume: 20
• Category: Article
• ISSN: 1095-6670
• DOI: 10.1002/jbt.20139

✦ Synopsis

Abstract

The action of carbenoxolone on hepatic energy metabolism was investigated in the perfused rat liver and isolated mitochondria. In perfused livers, carbenoxolone (200–300 μM) increased oxygen consumption, glucose production and glycolysis from endogenous glycogen. Gluconeogenesis from lactate or fructose, an energy‐dependent process, was inhibited. This effect was already evident at a concentration of 25 μM. The cellular ATP levels and the adenine nucleotide content were decreased by carbenoxolone, whereas the AMP levels were increased. In isolated mitochondria, carbenoxolone stimulated state IV respiration and decreased the respiratory coefficient with the substrates β‐hydroxybutyrate and succinate. The ATPase of intact mitochondria was stimulated, the ATPase of uncoupled mitochondria was inhibited, and the ATPase of disrupted mitochondria was not altered by carbenoxolone. These results indicate that carbenoxolone acts as an uncoupler of oxidative phosphorylation and, possibly, as an inhibitor of the ATP/ADP exchange system. The inhibitory action of carbenoxolone on mitochondrial energy metabolism could be contributing to induce the mitochondrial permeability transition (MPT), a key phenomenon in apoptosis. The results of the present study can explain, partly at least, the in vivo hepatotoxic actions of carbenoxolone that were found in a previous clinical evaluation. © 2006 Wiley Periodicals, Inc. J Biochem Mol Toxicol 20:230–240, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20139