Abstract
The hypoglycemic sulfonylureas glyburide and tolbutamide were found to be excellent inhibitors of the rat liver, heart, and skeletal muscle carnitine palmitoyltransferases, but glyburide was by far the most potent inhibitor. Carboxytolbutamide, a sulfonylurea that has no hypoglycemic effect, produced little or no inhibition of the enzyme from the three tissues examined. Fasting decreased the degree of inhibition of carnitine palmitoyltransferase by the sulfonylureas, and in genetically diabetic BB Wistar rats, a decrease in sensitivity was also clearly demonstrated. Initial rate kinetics of the inhibition of carnitine palmitoyltransferase indicated that glyburide inhibits noncompetitively with respect to palmitoyl-CoA while inhibition by malonyl-CoA was cooperatively competitive. Inhibition by malonyl-CoA was noncompetitive with respect to carnitine, but inhibition by glyburide was uncompetitive. These studies indicate that the hypoglycemic sulfonylureas inhibit carnitine palmitoyltransferase by a mechanism that is much different from inhibition by malonyl-CoA, but are, nevertheless, potent inhibitors of the enzyme. These results have important implications for energy metabolism in the liver and heart in relation to the use of sulfonylureas and for understanding the mechanism by which the sulfonylureas act to lower blood glucose, but there are also important implications of these results on the study of the metabolic regulation of fatty acid oxidation.
Highlights
The hypoglycemic sulfonylureas are a group of drugs that are currentlyused in the treatmentof non-insulin-dependent diabetes
An interesting aspect of the controlof carnitine palmitoyltransferase in relation to regulation of blood glucose is the recently discovered change that is brought about in the enzyme following treatment of rats withinsulinwhich results in adecreased capacity for hepatic fattyacid oxidation [15].These studies indicated that insulin lowered fatty acid oxidationrates by rapidly increasing the affinity of carnitinepalmitoyltransferase formalonylCoA
The results presented here indicate that glyburide and tolbutamide are potent inhibitoorfscarnitine palmitoyltransferase and thatglyburide, the more potent hypoglycemic drug, is the more potent inhibitor of carnitine palmitoyltransferase
Summary
The hypoglycemic sulfonylureas are a group of drugs that are currentlyused in the treatmentof non-insulin-dependent (type 11) diabetes. Activity of carnitine palmitoyltransferase that iesxpressed in A decreasein the sensitivitoyf hepatic carnitinepalmitoylintact mitochondria (on the outosfidthee mitochondrial inner transferase to inhibitionby malonyl-CoA occurs during fastmembrane), butglyburide wasmuch more potentas an inhib- ing [14,22] and with the onsoeft diabetes [15,23].In current itor than tolbutamide(Fig. 1).The concentration of tolbutam- experimentshepaticcarnitinepalmitoyltransferase in rats ide that produced50% inhibition of the enzyme was 35 times fasted for 72 h was inhibited somewhat less by 200 PM
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