Tolbutamide inhibits glucagon-induced phosphorylation of 6PF-2-K/Fru-2,6-P2ase in rat hepatocytes.
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.
Ayame
H
H
Third Department of Medicine, Yamaguchi University School of Medicine, Japan.
Matsutani
A
A
Inoue
H
H
Kaneko
T
T
Kaku
K
K
D000818:Animals; D005934:Glucagon / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D010732:Phosphofructokinase-1 / Q000378:metabolism*; D025481:Phosphofructokinase-2; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D014044:Tolbutamide / Q000494:pharmacology*
D005934:Glucagon; D014044:Tolbutamide; D025481:Phosphofructokinase-2; D010732:Phosphofructokinase-1; D010744:Phosphoric Monoester Hydrolases