Conjugation with glutathione and glucuronidation belong, to the most important reactions of phase II in biotransformation. Both pathways are in close interrelationship with glycogen metabolism: the ratio of reduced/oxidised glutathione (GSH/GSSG) affects several enzymes of glycogen metabolism, while glucuronidation gains the cofactor supply from glycogen breakdown. On this basis we have investigated the effect of different glutathione depleting agents (buthionine sulfoximine, diamide, menadione, acetaminophen) on the glucuronidation of p-nitrophenol in isolated murine hepatocytes. All of these compounds caused the alteration of GSH/GSSG ratio and the stimulation of glucuronidation. At the same time the elevation of cellular UDP-glucose content could be observed indicating a shift towards glycogen breakdown. In glycogendepleted hepatocytes these agents were unable to increase glucuronidation despite their effect on GSH/GSSG contents. In microsomal experiments different ratios of GSH/GSSG did not influence the p-nitrophenol UDPglucuronosyltransferase activity; moreover, neither of these agents enhanced the activity directly. We conclude that glutathione depletion stimulates glucuronidation by increasing Its UDP-glucuronic acid supply via an enhanced glycogenolysis in the liver. It is tempting to suggest that this way the ineffective conjugation Is partly compensated by an increased glucuronidation.
|Publication status||Published - Dec 1 1997|
ASJC Scopus subject areas
- Molecular Biology