Possible mechanism of proteolysis for the extrapancreatic action of tolbutamide.
In order to assess the mode of the extrapancreatic action of the sulfonylureas, we evaluated the contribution of a proteolytic mechanism for sulfonylurea action by analyzing the effects of a protease inhibitor on insulin- or tolbutamide-stimulated liver fructose-2,6-bisphosphate (F-2,6-P2) formation using isolated rat hepatocytes. The F-2,6-P2 level in hepatocytes was significantly increased by the addition of insulin or tolbutamide. The stimulatory effect of insulin on the F-2,6-P2 formation was most significant when its level was reduced by the addition of 2 microM of forskolin. Insulin action on F-2,6-P2 formation was inhibited by the addition of a protease inhibitor, p-tosyl-L-arginine methyl ester hydrochloride (TAME). Tolbutamide (2 mM) significantly increased hepatocyte F-2,6-P2 level (P less than 0.01 vs the control level). In the presence of TAME, the stimulatory effect of tolbutamide was also suppressed. The present data suggest that a proteolytic mechanism is important in both insulin and tolbutamide action on the F-2,6-P2 formation, and it may be hypothesized that, like insulin, the chemical mediator of tolbutamide action is formed proteolytically.
Matsutani
A
A
Third Department of Medicine, Yamaguchi University School of Medicine, Kogushi, Ube, Japan.
Kaku
K
K
Aoki
M
M
Mori
K
K
Matsuda
M
M
Kaneko
T
T
D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D005635:Fructosediphosphates / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014044:Tolbutamide / Q000494:pharmacology*; D014106:Tosylarginine Methyl Ester / Q000494:pharmacology*
D005635:Fructosediphosphates; D007328:Insulin; D005576:Colforsin; C027652:fructose 2,6-diphosphate; D014106:Tosylarginine Methyl Ester; D014044:Tolbutamide; D010450:Endopeptidases