Metabolism of 3,3'-diiodothyronine in rat hepatocytes: interaction of sulfation with deiodination.
Production of 3,3'-diiodothyronine (3,3'-T2) is an important step in the peripheral metabolism of thyroid hormone in man. The rapid clearance of 3,3'-T2 is accomplished to a large extent in the liver. We have studied in detail the mechanisms of this process using monolayers of freshly isolated rat hepatocytes. After incubation with 3,[3'-125I]T2, chromatographic analysis of the medium revealed two major metabolic routes: outer ring deiodination and sulfation. We recently demonstrated that sulfate conjugation precedes and in effect accelerates deiodination of 3,3'-T2. In media containing different serum concentrations the cellular clearance rate was determined by the nonprotein-bound fraction of 3,3'-T2. At substrate concentrations below 10(-8) M 125I- was the main product observed. At higher concentrations deiodination became saturated, and 3,3'-T2 sulfate (T2S) accumulated in the medium. Saturation of 3,3'-T2 clearance was found to occur only at very high (greater than 10(-6)M) substrate concentrations. The sulfating capacity of the cells exceeded that of deiodination by at least 20-fold. Deiodination was completely inhibited by 10(-4) M propylthiouracil or thiouracil, resulting in the accumulation of T2S while clearance of 3,3'-T2 was little affected. No effect was seen with methimazole. Hepatocytes from 72-h fasted rats showed a significant reduction of deiodination but unimpaired sulfation. Other iodothyronines interfered with 3,3'-T2 metabolism. Deiodination was strongly inhibited by 2 microM T4 and rT3 (80%) but little by T3 (15%), whereas the clearance of 3,3'-T2 was reduced by 27% (T4 and rT3) and 12% (T3). It is concluded that the rapid hepatic clearance of 3,3'-T2 is determined by the sulfate-transferring capacity of the liver cells. Subsequent outer ring deiodination of the intermediate T2S is inhibited by propylthiouracil and by fasting, essentially without an effect on overall 3,3'-T2 clearance.
D000818:Animals; D002452:Cell Count; D003470:Culture Media / Q000032:analysis; D004104:Diiodothyronines / Q000378:metabolism*; D005215:Fasting; D007455:Iodine / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D011441:Propylthiouracil / Q000494:pharmacology; D051381:Rats; D013431:Sulfates / Q000378:metabolism*; D013970:Thyronines / Q000378:metabolism*; D013974:Thyroxine / Q000494:pharmacology; D014284:Triiodothyronine / Q000494:pharmacology; D014285:Triiodothyronine, Reverse / Q000494:pharmacology
D003470:Culture Media; D004104:Diiodothyronines; D007457:Iodine Radioisotopes; D013431:Sulfates; D013970:Thyronines; D014284:Triiodothyronine; D014285:Triiodothyronine, Reverse; C030629:3,3'-diiodothyronine; D011441:Propylthiouracil; D007455:Iodine; D013974:Thyroxine