Phloretin inhibits cellular uptake and nuclear receptor binding of triiodothyronine in human hep G2 hepatocarcinoma cells.

Phloretin is an inhibitor of the mammalian glucose transporter and the iodothyronine-5'-deiodinase. We examined the effects of phloretin on cellular and nuclear uptake of [125I]T3 in cultured human Hep G2 hepatocarcinoma cells. The initial rate of T3 uptake was energy dependent and saturable with both a high affinity (Km = 3.6 nM) and a low affinity (Km = 503 nM) process. Phloretin produced a dose-dependent decrease in [125I]T3 uptake by Hep G2 cells (IC50 = 88 microM) and also inhibited nuclear uptake in intact cells and isolated nuclei. The solubilized nuclear receptor in the Hep G2 cells had a Kd of 0.14 nM for T3. Phloretin inhibited [125I]T3 binding to the solubilized nuclear receptor by competitive inhibition. Phlorizin, the beta-D-glucoside of phloretin, had no effect on T3 binding to the solubilized nuclear receptor. The inhibition of T3 cellular uptake and nuclear receptor binding is probably due to structural similarities between T3 and phloretin.