Reversible and irreversible inhibition of thyroid peroxidase-catalyzed iodination by thioureylene drugs.

Abstract

The mechanism of reversible and irreversible inhibition of thyroid peroxidase (TPO)-catalyzed iodination by thioureylene drugs was investigated using a model incubation system. The major observations may be summarized as follows. 1) TPO is inactivated by 1-methyl-2-mercaptoimidazole and propylthiouracil even in the presence of a relatively high concentration of iodide. The extent of this inactivation depends on the ratio of iodide to drug. 2) Spectral changes observed on oxidation of the drugs with the peroxidase-iodide system were very similar to those observed when the drugs were oxidized nonenzymatically with I3-. These findings support the view that oxidized iodine is an intermediate in TPO-catalyzed oxidation of the drugs. 3) Under conditions where TPO is largely inactivated, inhibition of iodination is complete and irreversible. Drug metabolism, on the other hand, occurs to a limited extent. 4) Under conditions where TPO is only partially inactivated, inhibition of iodination is transient (reversible). In this case, drug metabolism is extensive, and higher oxidation products (sulfate and sulfinic acid) are observed. Inhibition of iodination occurs only during the interval required to reduce the drug concentration to a low level. Thereafter, iodination may occur at a rate close to that observed in the absence of drug. Based on these and other observations, a scheme is presented to explain the mechanism of reversible and irreversible inhibition of iodination. In essence, the type of inhibition depends on the relative rates and extent of TPO inactivation and drug oxidation. These rates, in turn, depend primarily on the iodide to drug concentration ratio. A high ratio favors extensive drug oxidation and reversible inhibition. A low ratio favors TPO inactivation and irreversible inhibition.