Metabolism of triiodothyronine in rat hepatocytes.
The metabolism of T3 by isolated rat hepatocytes was analyzed by Sephadex LH-20 chromatography, HPLC, and RIA for T3 sulfate (T3S) and 3,3'-diiodothyronine (3,3'-T2). Type I iodothyronine deiodinase activity was inhibited with propylthiouracil (PTU), and phenol sulfotransferase activity by SO4(2-) depletion or with competitive substrates or inhibitors. Under normal conditions, labeled T3 glucuronide and I- were the main products of [3'-125I]T3 metabolism. Iodide production was decreased by inhibition (PTU) or saturation (greater than 100 nM T3) of type I deiodinase, which was accompanied by the accumulation of T3S and 3,3'-T2S. Inhibition of phenol sulfotransferase resulted in decreased iodide production, which was associated with an accumulation of 3,3'-T2 and 3,3'-T2 glucuronide, independent of PTU. Formation of 3,3'-T2 and its conjugates was only observed at T3 substrate concentrations below 10 nM. Thus, T3 is metabolized in rat liver cells by three quantitatively important pathways: glucuronidation, sulfation, and direct inner ring deiodination. Whereas T3 glucuronide is not further metabolized in the cultures, T3S is rapidly deiodinated by the type I enzyme. As confirmed by incubations with isolated rat liver microsomes, direct inner ring deiodination of T3 is largely mediated by a low Km, PTU-insensitive, type III-like iodothyronine deiodinase, and production of 3,3'-T2 is only observed if its rapid sulfation is prevented.
Rooda
S J
SJ
Department of Internal Medicine III, Erasmus University Medical School, Rotterdam, The Netherlands.
Otten
M H
MH
van Loon
M A
MA
Kaptein
E
E
Visser
T J
TJ
D000818:Animals; D002845:Chromatography; D002851:Chromatography, High Pressure Liquid; D004104:Diiodothyronines / Q000494:pharmacology; D005688:Galactosamine / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology; D009994:Osmolar Concentration; D010416:Pentachlorophenol / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D012457:Salicylamides / Q000494:pharmacology; D013431:Sulfates / Q000494:pharmacology; D014284:Triiodothyronine / Q000378:metabolism* / Q000494:pharmacology / Q000031:analogs & derivatives
D004104:Diiodothyronines; D009596:Nitrophenols; D012457:Salicylamides; D013431:Sulfates; D014284:Triiodothyronine; C037673:triiodothyronine sulfate; C015802:2,6-dichloro-4-nitrophenol; C030629:3,3'-diiodothyronine; D005688:Galactosamine; D010416:Pentachlorophenol; C031060:salicylamide