Interaction of Fluorescein Derivatives with Sulfonylurea Binding in Insulin-Secreting Cells

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Abstract
Recently evidence was presented that fluorescein derivatives (e.g. phloxine B) inhibit glibenclamide binding by occupation of a nucleotide-binding site at the ATP-sensitive potassium channel (KATP channel). However, this conclusion was inconsistent with the results of previous studies testing the effects of nucleotides on glibenclamide binding. To elucidate the interaction mode of fluorescein derivatives with sulfonylurea binding, the effect of phloxine B on binding of [3H]glibenclamide to microsomes obtained from a pancreatic beta-cell line (HIT-T15) was examined. Phloxine B inhibited specific binding of glibenclamide half-maximally at 3.2 mumol/l. The slope parameter for the displacement curve was close to one, suggesting a competitive interaction between both drugs. In accordance with this assumption 4 mumol/l phloxine B did not show an effect on the number of high-affinity binding sites but increased the apparent dissociation constant for glibenclamide by 3.1-fold and 30 mumol/l phloxine B did not alter the rate of dissociation of [3H]glibenclamide. Moreover, MgATP (300 mumol/l) significantly reduced the apparent affinity for binding of phloxine B to the sulfonylurea receptor. This finding resembled the action of MgATP on binding of sulfonylureas to their receptor site. It is concluded that fluorescein derivatives inhibit glibenclamide binding due to competition for the same site at the sulfonylurea receptor.

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