CHLOROGENIC ACID AND SYNTHETIC CHLOROGENIC ACID-DERIVATIVES - NOVEL INHIBITORS OF HEPATIC GLUCOSE-6-PHOSPHATE TRANSLOCASE

The enzyme system glucose-6-phosphatase (EC 3.1.3.9) plays a major rol e in the homeostatic regulation of blood glucose. It is responsible fo r the formation of endogenous glucose originating from gluconeogenesis and glycogenolysis. Recently, chlorogenic acid was identified as a sp ecific inhibitor of the glucose-6-phosphate translocase component (G1- 6-P translocase) of this enzyme system in microsomes of rat liver. Glu cose B-phosphate hydrolysis was determined in the presence of chloroge nic acid or of new synthesized derivatives in intact rat liver microso mes in order to assess the inhibitory potency of the compounds on the translocase component. Variation in the 3-position of chlorogenic acid had only poor effects on inhibitory potency. Introduction of lipohili c side chain in the 1-position led to 100-fold more potent inhibitors. Functional assays on isolated perfused rat liver with compound 29i, a representative of the more potent derivatives, showed a dose-dependen t inhibition of gluconeogenesis and glycogenolyosis, suggesting glucos e-6-phosphatase as the locus of interference of the compound for inhib ition of hepatic glucose production also in the isolated organ model. G1-6-P translocase inhibitors may be useful for the reduction of inapp ropriately high rates of hepatic glucose output often found in non-ins ulin-dependent diabetes.