A new method for the measurement of acute alterations in thyroxine deiodination rate in man

Abstract

A B S T R A C T A newly devised dual labeled iodine isotopic method is described for the detection and quantitation of alterations in thyroxine (T4) deiodination rate in man. This method employs the principle of a constant 'I infusion to serve as a reference source for the generation of 13I derived from the deiodination of T J-'I. Measurement of these two iodide isotopes are made in serially timed urine collections and are expressed in terms of a ratio value. Using this technique, it was possible to measure accurately the effects of a single dose of 6-propylthiouracil (6-PTU) in producing inhibition of T4 deiodination in euthyroid subjects. It was also possible to assess the time of onset, duration of action, and degree of inhibition produced by 6-PTU. Employing single doses of 6-PTU, ranging from 100 to 1000 mg, there was found to be a log dose relationship with a degree of inhibition observed in T4 deiodination. In control studies T4 deiodination rate was found to be constant for periods ranging up to 72 hr in normal ambulating subjects. The acute administration of many other agents was employed in an attempt to alter the T. deiodination rate. These included diphenylhydantoin, methimazole, triiodothyronine, thyroxine, thyroid stimulating hormone (TSH), adrenocorticotropin (ACTH), hydrocortisone, predinsolone, potassium iodide, epinephrine, and oxytocin. No detectable change in T4 deiodination rate was observed with these agents in the dosage ranges employed in this study. The lack of any observable alteration in the To deiodination rate in response to this array of drugs and hormones appears to indicate that the availability of T4 to intracellular sites of deiodination and possibly action is well modulated to resist abrupt changes. INTRODUCTIONA number of recent studies have been directed toward the measurement of changes in thyroxine (T4) disposal rate in man in response to both thyroidal and nonthyroidal disease, as well as to a variety of pharmacological and physiological stimuli (1-10). The close correlation generally observed between T4 disposal rate and peripheral hormonal action would appear to underscore the importance of these studies (11-16). The majority of these investigations have relied primarily upon the determination of labeled T4 turnover rates in either the plasma or the whole body.Since T4 disposal is the resultant of two rather distinct processes, i.e. (a) degradative deiodination and (b) biliary excretion, it would seem fundamental to the understanding of these previous studies to determine by which of the two routes To disposal was altered. This present investigation has been directed expressly at establishing a technique for the quantitative measurement of alterations in one of these mechanisms for thyroxine disposal, namely T4 deiodination rate. Additionally, the proposed method will allow measurement of the rapidity of onset, the duration of action, as well as the magnitude of changes in the T4 deiodination rate.

A new method for the measurement of thyroidal iodine release in man

“…These findings are consistent with the known action of I-in this regard. These changes in ratio values, produced after methimazole and potassium I-administration, were not due to changes in the deiodination rate of the reference thyroxine isotope (16). Subject C illustrated the effect of perchlorate administration on thyroid release.…”

“…Because the renal and extrarenal clearances of I-may vary spontaneously, a "~'I constant reference source was introduced into the system to negate this variable. The 'I could have been provided as a constant infusion as had been employed in our previous studies of T4 peripheral metabolism (16), but due to the regularity of T4 deiodination in vivo, T4-'8lI itself was used. In a sense, the deiodination of T4-'"I served as a type of biological constant infusion system.…”

“…As an outgrowth of recent studies conducted in our laboratory regarding the measurement of thyroxine deiodination rate (16), a new technique was developed for the detection of acute alterations in the rate of thyroidal iodine release. This study details the basic method employed in this technique as well as the general areas for its application in the study of both normal and abnormal thyroid function states.…”

Degradation of Thyroid Hormones by Phagocytosing Human Leukocytes

“…Methimazole, however, stimulates the deiodination of T3 and To by MPO and H202 or by intact leukocytes, and several studies have shown no effect of methimazole on To degradation in vivo (55,57,58). The possibility remains that a portion of the hormone metabolism in vivo is stimulated by methimazole, analogous to the MPO system, but is balanced by an inhibitory effect of methimazole on other hormone metabolizing systems, analogous to its effect on degradation by HRP or LPO and H202.…”

Reduction in extrathyroidal triiodothyronine production by propylthiouracil in man.

“…It inhibits many of the peripheral actions of thyroxine (T4) and slows the peripheral deiodination and, in some studies, the overall rate of degradation of T4 in both animals and man (1)(2)(3)(4)(5)(6). In contrast, while PTU has been shown to slow the fractional deiodination and degradation rate of triiodothyronine (T3) in animals (2, 6, 7), it has not been found to inhibit the biological actions of T3 (1).…”