Chlorogenic Acid and Synthetic Chlorogenic Acid Derivatives: Novel Inhibitors of Hepatic Glucose-6-phosphate Translocase
Received October 21, 1996 Abstract: The enzyme system glucose-6-phosphatase (EC 3.1.3.9) plays a major
role in the homeostatic
regulation of blood glucose. It is responsible for the formation
of endogenous glucose originating
from gluconeogenesis and glycogenolysis. Recently, chlorogenic
acid was identified as a specific
inhibitor of the glucose-6-phosphate translocase component (Gl-6-P
translocase) of this enzyme
system in microsomes of rat liver. Glucose 6-phosphate hydrolysis
was determined in the
presence of chlorogenic acid or of new synthesized derivatives in
intact rat liver microsomes 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 lipohilic 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-dependent inhibition of gluconeogenesis and
glycogenolyosis,
suggesting glucose-6-phosphatase as the locus of interference of the
compound for inhibition
of hepatic glucose production also in the isolated organ model.
Gl-6-P translocase inhibitors
may be useful for the reduction of inappropriately high rates of
hepatic glucose output often
found in non-insulin-dependent diabetes.
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