Regulation of glucuronidation by glutathione redox state through the alteration of UDP-glucose supply originating from glycogen metabolism

Abstract

The effect of altered redox state of glutathione was investigated on p-nitrophenol glucuronidation in isolated mouse hepatocytes. Decrease of GSH/GSSG ratio provoked by various agents caused increased glucuronidation which was accompanied by stimulated glycogenolysis and elevated UDP-glucose content. The stimulation of glycogenolysis and glucuronidation by glutathione consumption could be prevented by the reduction of oxidized glutathione with dithiothreitol and by the glycogenolysis inhibitor fructose. In permeabilized hepatocytes glycogen metabolism, bypassed by the addition of UDP-glucose, stimulated glucuronidation which was insensitive to glutathione depletion. In liver microsomes either UDP-glucuronosyltransferase activity or UDP-glucuronic acid transport was not influenced by GSH/GSSG ratio. These results suggest that alteration of the GSH/GSSG ratio regulates glucuronidation by affecting enzymes of the glycogen metabolism via the modification of UDP-glucuronate supply.