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Davidson
Thiourea and cyanamide as inhibitors of thyroid peroxidase: the role of iodide.Davidson B, Soodak M, Strout HV, Neary JT, Nakamura C, Maloof F. Endocrinology. 1979 Apr;104(4):919-24. [abstract only]
"Thiourea,
methylmercaptoimidazole, propylthiouracil, and thiouracil are all
potent inhibitors of thyroid peroxidase (TPO)-catalyzed
iodination. Unlike the cyclic thioureylenes, thiourea at 5 mM has
no effect on guaiacol oxidation. If iodide is added to guaiacol
assays containing thiourea, enzyme activity is lost. The latter
observation may be explained as follows. In the presence of
iodide, the iodinating species [TPO.Ioxid], oxidizes thiourea to
formamidine disulfide. This product decomposes to cyanamide at
neutral pH. We have shown cyanamide to be an inhibitor of the
peroxidative and iodinating functions of TPO. Studies in rats
demonstrate that doses of thiourea which completely inhibit in
vivo protein-bound iodine formation have no irreversible effect
on TPO, as measured by guaiacol peroxidation after removal of the
thyroids. The major in vivo action of cyanamide is similar to
that of thiourea. The data suggest that the primary in vivo and
in vitro mode of action of thiourea is the reversible Ioxid-trapping
mechanism. The anomalous inhibition of guaiacol peroxidation seen
in the presence of thiourea plus iodide derives from the
formation of formamide disulfide, followed by its nonenzymic
decomposition to cyanamide."
The irreversible inactivation of thyroid peroxidase by methylmercaptoimidazole, thiouracil, and propylthiouracil in vitro and its relationship to in vivo findings.Davidson B, Soodak M, Neary JT, Strout HV, Kieffer JD, Mover H, Maloof F. Endocrinology. 1978 Sep;103(3):871-82. [abstract only]
"A reinvestigation of the mechanism of action
of methylmercaptoimidazole, propylthiouracil, and thiouracil on
thyroid peroxidase (TPO) was undertaken. A preliminary incubation of
TPO and H2O2 with methylmercaptoimidazole, propylthiouracil, or
thiouracil was carried out in the absence of oxidizable substrates
(i.e. I- or guaiacol). This incubation resulted in irreversible
inactivation of TPO. The extent of inactivation could be determined
after removal of the drug by gel filtration or by dilution into the
assay mixture. Preincubation, as above, in the presence of iodide or
thiocyanate prevented the irreversible inactivation of TPO. Rats
receiving doses of these drugs which completely inhibited
protein-bound iodine formation showed normal levels of TPO in their
thyroid glands 30 min after drug administration. These findings
suggest that the initial in vivo action of these drugs is to block
iodination by trapping oxidized iodide, not by acting as "general
inhibitors" of the TPO." |
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