Effects of inhibition of type I iodothyronine deiodinase and phenol sulfotransferase on the biliary clearance of triiodothyronine in rats.
Recent studies using isolated rat hepatocytes have indicated that the bioactive form of thyroid hormone, T3, is metabolized in liver predominantly by conjugation with glucuronic acid or sulfate. In contrast to T3 itself and the stable glucuronide, T3 sulfate is rapidly degraded by successive deiodination of the tyrosyl and phenolic rings. In the present study we have investigated the biliary excretion of T3 metabolites in male Wistar rats under pentobarbital anesthesia. The animals were injected iv with 1) saline, 2) the deiodinase inhibitor propylthiouracil (PTU; 1 mg/100 g BW), 3) the phenol sulfotransferase inhibitor dichloronitrophenol (2.6 mumol/100 g BW), or 4) a combination of both drugs. After 15 min, 10 muCi [125I]T3 were administered iv, and bile was collected for 30-min periods until 4 h after tracer injection. Secretory products were analyzed by HPLC. In control animals, 22.4% of the dose was excreted in bile mainly in the form of T3 glucuronide. In PTU-treated rats biliary excretion was increased to 36.0% of the dose (P less than .001) due to a dramatic increase in the sulfates of T3 and 3,3'-diiodothyronine. Dichloronitrophenol by itself had no effect on the biliary clearance of T3, but greatly inhibited PTU-induced excretion of sulfates. These results strongly suggest that sulfation and subsequent deiodination is an important pathway of T3 metabolism in vivo.
Department of Internal Medicine, Erasmus University Medical School, Rotterdam, The Netherlands.
W W
WW
de Herder
F
F
Bonthuis
M
M
Rutgers
M H
MH
Otten
M P
MP
Hazenberg
T J
TJ
Visser
D000818:Animals; D015239:Arylsulfotransferase; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008297:Male; D009596:Nitrophenols / Q000494:pharmacology*; D011441:Propylthiouracil / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013466:Sulfurtransferases / Q000037:antagonists & inhibitors*; D014284:Triiodothyronine / Q000378:metabolism*
D009596:Nitrophenols; D014284:Triiodothyronine; C015802:2,6-dichloro-4-nitrophenol; D011441:Propylthiouracil; D007453:Iodide Peroxidase; D013466:Sulfurtransferases; D015239:Arylsulfotransferase