COMPETITIVE-INHIBITION OF THYROID-HORMONE UPTAKE INTO CULTURED RAT-BRAIN ASTROCYTES BY BILIRUBIN AND BILIRUBIN CONJUGATES

Thyroid hormone (TH) metabolism is altered in cases of unconjugated hyperbilirubinemia. These effects might involve inhibition of TH uptake by their target cells. Astrocytes, which are in close contact with the membranes of brain capillaries, might be the first brain cells to come into contact with bilirubin. Cultured rat brain astrocytes were used as a model to study the effects of bilirubin and bilirubin analogues on TH uptake. The initial uptake of [I-125]T-3 and [I-125]T-4 was inhibited by unconjugated bilirubin, biliverdin, ditaurobilirubin and bilirubin glucuronides. The inhibition: of T-3 uptake by the bilirubin analogues was competitive. The K-i values were: unconjugated bilirubin (31 mu M), biliverdin (48 mu M), ditaurobilirubin (2.5 mu M) and bilirubin glucuronides (1.2 mu M). This Last value is similar to the K-m of T-3 transport (0.4 mu M), indicating that bilirubin glucuronides have a high affinity for the TH transport system. By contrast, the uptakes of [H-3]tryptophan and [H-3]glutamine were not inhibited. These results suggest that the astrocyte plasma membrane bears specific bilirubin-interaction sites that are closely related to the TH transport system. However, uptake of [C-14]bilirubin by cultured astrocytes was a non-saturable process. Binding of bilirubin to the astrocyte plasma membrane may inhibit the TH uptake and impair their metabolism and their action on the intracellular targets.