Selenouracil derivatives are potent inhibitors of the selenoenzyme type I iodothyronine deiodinase.
Type I iodothyronine deiodinase (ID-I) is a selenoenzyme, which is important for the conversion of the prohormone thyroxine (T4) to the bioactive thyroid hormone 3,3',5-triiodothyronine (T3). 2-Thiouracil derivatives inhibit ID-I by interaction with an enzyme form generated during catalysis. We have now tested the potential inhibitory effects of the selenocompounds 6-methyl- (MSU) and 6-propyl-2-selenouracil (PSU) in comparison with their thioanalogs 6-methyl- (MTU) and 6-propyl-2-thiouracil (PTU) on rat liver ID-I activity using 3,3',5-triiodothyronine (reverse T3, rT3) as substrate and dithiothreitol (DTT) as cofactor. All compounds showed dose-dependent inhibition of ID-I with IC50 values of 1, 0.5, 0.4 and 0.2 microM for MTU, MSU, PTU and PSU, respectively. Our results further suggest that these inhibitions are uncompetitive with substrate and competitive with cofactor. The high potency of selenouracils may be due to reaction with a substrate-induced enzyme selenenyl iodide intermediate under formation of a stable enzyme-selenouracil diselenide.
Visser
T J
TJ
Department of Internal Medicine III, Erasmus University Medical School, Rotterdam, The Netherlands.
Kaptein
E
E
Aboul-Enein
H Y
HY
D000818:Animals; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008779:Methylthiouracil / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000201:enzymology*; D015394:Molecular Structure; D016566:Organoselenium Compounds / Q000494:pharmacology*; D011441:Propylthiouracil / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
D007527:Isoenzymes; D016566:Organoselenium Compounds; C079082:6-propyl-2-selenouracil; C079083:6-methyl-2-selenouracil; D014498:Uracil; D011441:Propylthiouracil; D007453:Iodide Peroxidase; D008779:Methylthiouracil