5'-Deiodination in rat hepatocytes: effects of specific flavonoid inhibitors.
5'-Deiodination of T4 or rT3 in the presence of flavonoids was studied in freshly isolated suspended rat hepatocytes. Flavonoids, a novel group of synthetic deiodinase inhibitors, were designed to act as T4 antagonists. 5'-Deiodination of the prohormone T4 to the thyromimetically active T3 is an essential first step in controlling thyroid hormone action. Hepatocytes were incubated with either 2 microM T4 or 2 microM [125I]rT3 as 5'-deiodinase substrates in the absence and presence of inhibitors (0.1-100.0 microM). T3 production from T4 was determined by T3 RIA, and [125I]iodide release from [125I]rT3 was alternatively used as a technically more simple and rapid but sensitive deiodinase assay. Aurones and flavones inhibited both T4 5'-deiodination and rT3 5'-deiodination, with half-maximal inhibitor concentrations from 3-45 microM. Aurones were equally potent in both assays. 3-Methyl-flavones, designed as rT3 analogs, were more active by a factor of 3-5 with T4 5'-deiodination than with rT3 5'-deiodination, with the exception of one relatively cell-toxic compound. Hepatocyte viability was controlled by trypan blue dye exclusion as well as by measuring gluconeogenesis from exogenously added 10 mM lactate. Some of the flavonoids inhibited gluconeogenesis at concentrations that had no effect on trypan blue dye exclusion. Flavonoid inhibitors reduce 5'-deiodinase activity in intact hepatocytes in concentrations equimolar to those of substrates. Therefore, synthetic flavonoids may be suitable substances for further study of iodothyronine physiology or, after modification, could be useful as a new class of antiiodothyronine drugs.
Spanka
M
M
Abteilung Klinische Endokrinologie, Medizinische Hochschule Hannover, West Germany.
Hesch
R D
RD
Irmscher
K
K
Köhrle
J
J
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D002470:Cell Survival; D055598:Chemical Phenomena; D002621:Chemistry; D005419:Flavonoids / Q000494:pharmacology*; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors; D007455:Iodine / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship; D013974:Thyroxine / Q000378:metabolism; D014284:Triiodothyronine / Q000096:biosynthesis
D001572:Benzofurans; D005419:Flavonoids; D014284:Triiodothyronine; C057452:3-methyl-4',6-dihydroxy-3',5'-dibromoflavone; D007455:Iodine; D007453:Iodide Peroxidase; D013974:Thyroxine