Abstract
The mechanism by which proglycosyn (LY 177,507) stimulates glycogen synthesis in isolated hepatocytes [Harris, R. A., Yamanouchi, K., Roach, P. J., Yen, T. T., Dominiani, S. J. & Stephens, T. W. (1989) J. Biol. Chem. 264, 13674-13680] has been investigated. When incubated in the presence of hepatocytes, proglycosyn was metabolized to an O-demethylated glucuronidated derivative, as determined by fast-atom-bombardment mass spectrometry and enzymic analysis. This metabolite accumulated almost linearly inside the cells to reach a concentration of approximately 3 mumol/g protein after 50 min, without apparent release into the medium. In confirmation of previous work, proglycosyn decreased the level of phosphorylase a and increased that of synthase a in hepatocytes. Washing of cells incubated with proglycosyn for 30 min considerably decreased the concentration of the drug without significantly modifying the intracellular concentration of the metabolite and the activation state of glycogen synthase. Several compounds bearing structural analogy with proglycosyn were also tested for their effect on glycogen metabolism. At millimolar or submillimolar concentrations, resorcinol, m-anisidine, phenol, 3-hydroxyacetophenone, and 3-acetamidophenol, although not 4-acetamidophenol, stimulated the incorporation of [14C]glucose into glycogen, decreased the level of phosphorylase a and increased the level of synthase a. In the case of phenol, the effect on the glycogen enzymes paralleled the intracellular accumulation of phenylglucuronide. Furthermore, ethanol and D-galactosamine, which decreased the conversion of phenol to phenylglucuronide and the intracellular concentration of phenylglucuronide, counteracted the effect of phenol on the synthase and on the phosphorylase. From these results, it is suggested that the effect of proglycosyn and of simpler phenol derivatives is mediated by glucuronidated metabolites, which act on an intracellular target.
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