Interaction of Mixed‐Function Oxidation with Biosynthetic Processes: 1. Inhibition of Gluconeogenesis by Aminopyrine in Perfused Rat Liver

Abstract

Gluconeogenesis from lactate was studied in perfused livers from phenobarbital‐pretreated rats fasted for 24 h. Maximal rates of glucose production obtained with lactate concentrations of more than 2 mM were suppressed to about 50% following the addition of aminopyrine, a substrate for NADPH‐utilizing mixed‐function oxidations. Submaximal rates (i.e. with 0.5–2 mM lactate) or gluconeogenesis from dihydroxyacetone were only slightly affected by aminopyrine, whereas no inhibition was observed at low gluconeogenic rates. The data are consistent with the following hypothesis. In the presence of active NADPH‐utilizing processes (such as mixed‐function oxidation of aminopyrine) a futile cycle involving malic enzyme occurs in the pathway of gluconeogenesis which is compensated for by an increased flux through the pyruvate carboxylase reaction. Thus, gluconeogenesis is suppressed when maximal activity of pyruvate carboxylase is reached. It is assumed that the observed inhibition of gluconeogenesis is not specific for mixed‐function oxidation, but may be an example for a more general mechanism of metabolic interdependences involving the extramitochondrial NADPH pool.