AJP - Endocrinology and Metabolism, Vol 268, Issue 3 E391-E396, Copyright © 1995 by American Physiological Society
Tolbutamide inhibits glucagon-induced phosphorylation of 6PF-2-K/Fru-2,6-P2ase in rat hepatocytes
H. Ayame, A. Matsutani, H. Inoue, T. Kaneko and K. Kaku
Third Department of Medicine, Yamaguchi University School of Medicine, Japan.
In previous studies, we demonstrated that tolbutamide inhibits a
phosphorylation of hepatic 6-phosphofructo-2-kinase
(6PF-2-K)/fructose-2,6-bisphosphatase (Fru-2,6-P2ase) catalyzed by the
adenosine 3',5'-cyclic monophosphate-dependent protein kinase in a
reconstruction system using the purified enzyme from the rat liver. In the
current study, to assess a role of tolbutamide on hepatic
6PF-2-K/Fru-2,6-P2ase physiologically, we used intact rat hepatocytes and
examined effects of tolbutamide on a phosphorylation of the bifunctional
enzyme in the presence of glucagon. Glucagon induced a rapid
phosphorylation of hepatic 6PF-2-K/Fru-2,6-P2ase accompanied by an
inhibition of 6PF-2-K activity and a stimulation of Fru-2,6-P2ase activity
in a dose-dependent manner. Tolbutamide inhibited glucagon-induced
phosphorylation of the bifunctional enzyme protein in a dose-dependent
manner. By adding 2 mM tolbutamide, reduced activity of 6PF-2-K and
increased activity of Fru-2,6-P2ase in the presence of 10(-9) M glucagon
were partially restored. The present results suggest the possibility that
tolbutamide modulates the activity of hepatic 6PF-2-K/Fru-2,6-P2ase through
inhibiting a phosphorylation of the enzyme protein. The counterregulatory
influence of tolbutamide on the effect of glucagon suggests a possible
mechanism for the extrapancreatic effect of sulfonylurea drugs.
