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.

Whereas thyrotropin releasing hormone is rapidly and extensively degraded by plasma of adult rats, no appreciable loss of biological or immunological activity is caused by plasma from rats 4 or 16 days old. The plasma of neonatal rats does not appear to contain an inhibitor of thyrotropin releasing hormone peptidase or a peptidase with altered substrate affinity. The development of an active peptidase in rat plasma suggests a physiological role for inactivation of thyrotropin releasing hormone.

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