Metabolic effects of hypoglycemic sulfonylureas—VI: Effects of chlorpropamide and carbutamide on ketogenesis and on mitochondrial redox state in the isolated perfused rat liver

Abstract

The effect of 5 mM chlorpropamide and 5 mM carbutamide on fatty acid oxidation in the perfused rat liver was studied. Chlorpropamide as well as carbutamide inhibited endogenous lipid oxidation to ketone bodies. Chlorpropamide had no effect on ketogenesis from exogenously added octanoate, but inhibited ketone body production from a single dose of oleate. Ketogenesis from a continuous oleate infusion was reduced by chlorpropamide during the first 15 min of infusion but was unaffected during the next 45 min studied. Carbutamide did not decrease ketogenesis during oleate infusion. The uptake of octanoate and oleate remained unchanged in the presence of both drugs. Chlorpropamide caused a stimulation of oxygen consumption in the absence of fatty acid substrates but was unable to alter oleate-stimulated respiration. Chlorpropamide, but not carbutamide, stimulated oligomycin-inhibited respiration although to a lesser degree than 2,4-dinitrophenol. Krebs cycle flux during oleate infusion was slightly stimulated by chlorpropamide. Mitochondrial redox state, as measured by the β-hydroxybutyrate/acetoacetate ratio in the perfusate, was markedly lowered by chlorpropamide in the octanoate and oleate experiments. The lactate/pyruvate ratio was unaffected by chlorpropamide. Carbutamide did not produce any change compared with control experiments. From these experiments it is concluded that chlorpropamide and carbutamide inhibit endogenous lipid oxidation by interfering with hepatic triglyceride lipase activity. Changes in oxygen uptake and in mitochondrial redox state caused by chlorpropamide are attributed to the uncoupling activity of this drug.