thiouracil and 6-n-propyluracil

Hyperthyroidism is the result of uncontrolled overproduction of the thyroid hormones. One of the mostly used antithyroid agents is 6-

Topics: Animals; Antithyroid Agents; Binding Sites; Disease Models, Animal; Hydrophobic and Hydrophilic Interactions; Hyperthyroidism; Lactoperoxidase; Models, Molecular; Rats; Structure-Activity Relationship; Thiouracil; Triiodothyronine; Uracil

In this paper, the activity of horseradish peroxidase was further determined in the presence of several uracil derivatives. The rate of guaiacol peroxidation decreases in presence of 2-thiouracil and of 6-n-propyl-2-thiouracil, but is not changed by 6-n-propyluracil nor uracil. Thus, thiouracils inhibit horseradish peroxidase in a noncompetitive form. The binding of 6-n-propyl-2-thiouracil, 2-thiouracil, 6-n-propyluracil and uracil with horseradish peroxidase shows difference spectra due to changes in the environment of heme group in peroxidase. Then, the binding sites for these uracil derivatives are in an hydrophobic pocket at the heme periphery of peroxidase. The lesser binding rates were for uracil and propyluracil, which did not inhibit the peroxidase activity. These results point to the thiol group in uracils as responsible for the inhibition of peroxidase activity through interaction with an allosteric binding site, in peroxidase heme environment.

Topics: Antithyroid Agents; Horseradish Peroxidase; Protein Binding; Spectrophotometry, Ultraviolet; Thiouracil; Uracil

The binding interactions of some thioureylene compounds to human serum albumin were studied in vitro by ultraviolet spectroscopy and equilibrium dialysis. Binding of 6-n-propyl-2-thiouracil, 6-n-benzyl-2-thiouracil and 2-thiouracil to human serum albumin results in a red shift of the ultraviolet absorption maximum, suggesting that the binding site is a hydrophobic area of the protein. Bindings of 6-n-propyl-2-thiouracil and 6-n-benzyl-2-thiouracil to human serum albumin are characterized by two classes of sites while 6-n-propyl-uracil and 2-thiouracil bind to one low-affinity binding site. In addition, an identification of those sites was performed by measuring the displacement of these drugs. The data show that the moderate-affinity site is common with the warfarin site while the low-affinity site is likely to be shared by benzodiazepines. It is concluded that the binding is enhanced by the hydrophobicity of the substituent in the thioureylene compounds, and it is further shown that thiol-group substitutions in the thioureylene ring will weaken the binding.

Topics: Antithyroid Agents; Diazepam; Humans; Propylthiouracil; Serum Albumin; Spectrophotometry, Ultraviolet; Thiouracil; Uracil; Warfarin