Effects of Propylthiouracil and Thiouracil on the Metabolism of Thyroxine and Several of Its Derivatives by Rat Kidney Slices<i>in Vitro</i>1

Braverman, Lewis E.; Ingbar, Sidney H.

doi:10.1210/endo-71-5-701

Cited by 24 publications

(9 citation statements)

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“…The extrathyroidal effects of propylthiouracil have been known for over a decade (Escobar del Rey & Morreale de Escobar, 1961) and Braverman & Ingbar (1962) found inhibition of T4 to T3 conversion by propylthiouracil in kidney slices, which we can confirm by showing a significant inhibition of T4 to T3 conversion by propylthiouracil at concentrations of lo-' mol/l and above. Propylthiouracil does not affect uptake of T4 into the cells and the inhibitory effect is not due to T4 depletion, as the total recoverable T4 was not reduced by propylthiouracil.…”

Section: Discussionsupporting

confidence: 81%

The Formation of Tri-Iodothyronine and Reverse Triiodothyronine from Thyroxine in Isolated Rat Renal Tubules

et al. 1978

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1. Conversion of thyroxine into tri-iodothyronine and reverse tri-iodothyronine in intact cells was studied with isolated renal tubules prepared by collagenase digestion. 2. Conversion of thyroxine into tri-iodothyronine and reverse tri-iodothyronine increased progressively for at least 90 min. 3. Studies of tri-iodothyronine production from increasing amounts of thyroxine revealed that the thyroxine to tri-iodothyronine conversion is saturable. 4. Iodine and carbimazole had no effect on the thyroxine to tri-iodothyronine conversion. 5. 6-Propyl-2-thiouracil had a direct non-competitive inhibitory effect on the conversion of thyroxine into tri-iodothyronine with a 75% inhibition of the conversion at a propylthiouracil concentration within the therapeutic range in vivo. Propylthiouracil also inhibited the net formation of reverse tri-iodothyronine from thyroxine at a similar propylthiouracil concentration, as well as inhibiting the subsequent degradation of reverse tri-iodothyronine.

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Section: Discussionsupporting

confidence: 81%

The Formation of Tri-Iodothyronine and Reverse Triiodothyronine from Thyroxine in Isolated Rat Renal Tubules

et al. 1978

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“…The major site of action of 6-PTU on the peripheral tissue alteration of T4 deiodination appears most likely to be the liver, although similar effects have been observed in kidney slices (18). Since the liver contains deiodinating as well as conjugating enzyme systems for thyroxine, one may speculate that if the hepatic cells were unable to deiodinate T4 the alternative route of glucuronide conjugation and biliary excretion would then be utilized (19).…”

Section: Methodsmentioning

confidence: 88%

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

Nicoloff¹

1970

J. Clin. Invest.

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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.

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“…This extrathyroidal action is independent of the first effect (14). The inhibition of peripheral deiodination is associated with a decrease in the biologic effectiveness of administered T4 as measured by a decrease in metabolic rate or induction of oxidative enzymes in vivo (15)(16)(17)(18)(19)(20) and in vitro (21)(22)(23) and an increase in thyrotropin (TSH) secretion (24)(25)(26)(27)(28). The thiocarbamide drugs that decrease To deiodination are the ones that also decrease its metabolic effectiveness (14).…”

Section: Introductionmentioning

confidence: 99%

“…The PTU-induced decrease in the peripheral deiodination of T4 to T3 has been shown to be associated with a decrease in biologic activity of T4 in vivo (15)(16)(17)(18)(19)(20) and in vitro (21)(22)(23). Methimazole and other thiocarbamide drugs which do not affect the deiodination of To do not interfere with its metabolic effectiveness (14).…”

Section: Introductionmentioning

confidence: 99%

Propylthiouracil blocks extrathyroidal conversion of thyroxine to triiodothyronine and augments thyrotropin secretion in man.

Geffner¹,

Azukizawa²,

Hershman³

1975

J. Clin. Invest.

188

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A B S T R A C T Propylthiouracil (PTU) inhibits peripheral deiodination of thyroxine (T4) and triiodothyronine (T3) and decreases the metabolic effectiveness of T4 in animals. To assess the effect of PTU on extrathyroidal conversion of T4 to Ta in man, 15 studies were performed in 7 athyreotic patients treated with 100 or 200 Ag of L-T4 daily for 1 mo before the addition of PTU, 250 mg every 6 h for 8 days. Serum T3, T4, and thyrotropin (TSH) were measured daily by radioimmunoassay; serum TSH response to 500-ig thyrotropin-releasing hormone (TRH) was measured before and on the last day of giving PTU.On the 100-Ag L-T4 dose, serum T3 fell from 120±5 The data suggest that PTU blocks extrathyroidal conversion of To to Ts, thus increasing pituitary TSH secretion and augmenting the TSH response to TRH.

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Effects of Propylthiouracil and Thiouracil on the Metabolism of Thyroxine and Several of Its Derivatives by Rat Kidney Slicesin Vitro1

Cited by 24 publications

References 1 publication

The Formation of Tri-Iodothyronine and Reverse Triiodothyronine from Thyroxine in Isolated Rat Renal Tubules

The Formation of Tri-Iodothyronine and Reverse Triiodothyronine from Thyroxine in Isolated Rat Renal Tubules

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

Propylthiouracil blocks extrathyroidal conversion of thyroxine to triiodothyronine and augments thyrotropin secretion in man.

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