Effect of tolbutamide and glyburide on cAMP-dependent protein kinase activity in rat liver cytosol.
The effect of sulfonylureas tolbutamide and glyburide on adenylate cyclase- and cAMP-dependent protein kinase (A-kinase) was examined in rat liver cytosol. Both tolbutamide and glyburide inhibited the A-kinase activity in a dose-dependent manner. Half-maximal inhibition was obtained at 10 mM with tolbutamide and at 0.2 mM with glyburide, indicating that glyburide was 50-fold as potent as tolbutamide. Neither tolbutamide nor glyburide affected [3H]cAMP binding to the protein kinase, but both inhibited the activity of catalytic units of the A-kinase. Lineweaver-Burk double-reciprocal plots revealed that the inhibitory effects of these drugs were noncompetitive with respect to the protein substrate histone, as well as to the phosphate-donor substrate ATP. Thus, tolbutamide and glyburide inhibited the A-kinase activity in rat liver cytosol, and it was suggested that, through the inhibition of A-kinase, the sulfonylureas would affect the carbohydrate metabolism in the liver. In fact, the relative potencies of these two drugs on A-kinase activity corresponded well with those of their reported antidiabetic effects.
Okuno
S
S
Second Department of Internal Medicine, Osaka City University Medical School, Japan.
Inaba
M
M
Nishizawa
Y
Y
Inoue
A
A
Morii
H
H
D000255:Adenosine Triphosphate / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology*; D003600:Cytosol / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014044:Tolbutamide / Q000494:pharmacology*
D006657:Histones; D000255:Adenosine Triphosphate; D014044:Tolbutamide; D000242:Cyclic AMP; D011494:Protein Kinases; D000262:Adenylyl Cyclases; D005905:Glyburide