Iodine-Containing Compounds of Extrathyroidal Tissues*

A B S T R A C T Administration of phenobarbital, which acts exclusively on cellular sites, results in an augmentation of the liver/plasma concentration ratio of L-thyroxine (T4) in rats but no change in the liver/plasma concentration ratio of L-triiodothyronine (T3). Whereas phenobarbital stimulates the fecal clearance rate both of T3 and T4, it increases the deiodinative clearance rate of T4 only. These findings suggest basic differences in the cellular metabolism of T3 and T4. Further evidence pointing to cellular differences was obtained from a comparison of the distribution and metabolism of these hormones with appropriate corrections for the effect of differential plasma binding. The percentage of total exchangeable cellular T4 within the liver (28.5) is significantly greater than the corresponding percentage of exchangeable cellular T3 within this organ (12.3). Extrahepatic tissues bind T3 twice as firmly as T4. The cellular metabolic clearance rate (= free hormone clearance rate) of T3 exceeds that of T4 by a factor 1.8 in the rat. The corresponding ratio in man, 2.4, was determined by noncompartmental analysis of turnover studies in four individuals after the simultaneous injection of T4-'I and T3-2"I. The greater cellular metabolic clearance rate of T3 both in rat and man may be related to the higher specific hormonal potency of this iodothyronine.

Section: Discussionsupporting

confidence: 92%

Differences in primary cellular factors influencing the metabolism and distribution of 3,5,3′-L-triiodothyronine and L-thyroxine

Oppenheimer¹,

Schwartz²,

Shapiro³

et al. 1970

“…This, however, does not appear to be the case. In long-term iodine equilibrated rats studied by Heninger, Larson, and Albright (19), the concentration ratio (tissue/plasma) was 7.6 for kidney and 2.9 for liver. In recent distribution studies in our laboratory (13), the equilibrium value of the distribution ratio of isotopically labeled T3 between kidney and plasma was 8.3, and between liver and plasma 5.3.…”

Section: Resultsmentioning

confidence: 87%

“…It is possible to calculate the proportion of total body T3 which is due to metabolic conversion from T4, if we assume that the nonradioactive T4 and T3 concentrations determined by isotopic 'I equilibration in the rat are 33.5 ng/ml and 1.15 ng/ml respectively (19). Let us at the same time assume an extrathyroidal T4 space of 16.4 mV100 g, an extrathyroidal T3 space of 165 ml/100 g, mean fractional T4 and T3 removal rates of 1.032/day and 2.064/day (13).…”

Section: Resultsmentioning

confidence: 99%

Quantitation of extrathyroidal conversion of l-thyroxine to 3,5,3′-triiodo-l-thyronine in the rat

Schwartz¹,

Surks²,

Oppenheimer³

1971

178

A B S T R A C T Studies of the rate of extrathyroidal conversion of thyroxine (T4) to 3,5,3'-triiodo-L-thyronine (T3) were carried out in rats. Total body homogenates were prepared and extracted with ethanol 48, 72, and 96 hr after the intravenous injection of 'I-T4. 'I-T3 was added, and the paper chromatographic purification of T3 was effected by serial elution and rechromatography in three paper and one thin-layer cycles. The ratio of 'I-T3 and 'I-T3 counting rates in the final chromatograms, which was identical in three different paper chromatography systems, was used to calculate the proportion of 'I-T3 to 'I-T4 in the original homogenates. In order to discount the effects of in vitro monodeiodination of T4 during extraction and chromatography, we killed control animals immediately after injection of 'I-T4 and processed them in a similar fashion to the experimental groups. The average ratio of 'I-T3 to 'I-T4 in carcass extracts of animals killed between 48 and 96 hr after isotopic injection was 0.08 whereas the average ratio of 'I-T3 to 'I-T4 in chromatograms of control animals was 0.01. On the bais of the proposed model, calculations indicated that about 17% of the secreted T4 was converted to T3. Assuming values cited in the literature for the concentration of nonradioactive T3 in rat plasma, these findings would suggest that about 20% of total body T3 is derived by conversion from T4. Moreover, since previous estimates have suggested that in the rat, T3 has about 3 to 5 times greater biologic activity than T4, these results also raise the possibility that the hormonal activity of T4 may be dependent in large part on its conversion to T3.A necessary assumption in calculating T4 to T3 conversion in this and other studies is that the 3' and 5' positions are randomly labeled with radioiodine in Dr. Oppenheimer is a Career Scientist of the Health Research Council of New York City (Award I-222).Received for publication 30 November 1970 and in revised form 18 January 1971.phenolic-ring iodine-labeled T4. Evidence supporting this assumption was obtained in the rat by comparing the amount of labeled T3 produced after injection of phenolic and nonphenolic-ring iodine-labeled T4: INTRODUCTIONSince the initial identification of triiodothyronine (T3) in human plasma by Gross and Pitt-Rivers (1), a number of studies have dealt with the source of this hormone. In laboratory animals, the concentration of T3 is higher in the thyroid venous effluent than in the arterial blood, suggesting its secretion by the gland (2, 3). On the other hand, a number of studies have focused on the possibility of the extrathyroidal conversion of thyroxine (T4) to T3 (4-7). A claim that T4 was converted to T3 in man (8) was subsequently retracted (9) and the likelihood of metabolically significant conversion of T4 to T3 was generally discounted.More recently, the possibility of peripheral conversion of T4 to T3 was revived by the report of Braverman, Ingbar, and Sterling (10) that demonstrated the presence of T3 in the plasma of athyreotic ...

“…Endogenous T4 concentrations in rat liver have been estimated to be 11.05±1.63 ng/g whole liver (41), which would be <5 nmol/liter of homogenate, < 1% of the T4 added in the present experiments. No informationi is available about endogenous hepatic rT3 concentrations.…”

mentioning

confidence: 63%

Iodothyronine Metabolism in Rat Liver Homogenates

Kaplan¹,

Utiger²

1978

324

131

A B S T R A C T To investigate mechanisms of extrathyroidal thyroid hormone metabolism, conversion of thyroxine (T4) to 3,5,3'-triiodothyronine (T3) and degradation of 3,3',5'-triiodothyronine (rT3) were studied in rat liver homogenates. Both reactions were enzymatic. For conversion of T4 to T3, the Km of T4 was 7.7 ,uM, and the Fasting resulted in inhibition of T4 to T3 conversion and of rT3 degradation by rat liver homogenates which was reversible after refeeding. Serum T4, T3, and thyrotropin concentrations fell during fasting, with no decrease in serum protein binding as assessed by a T3-charcoal uptake. There was no consistent change in serum rT3 concentrations. Dexamethasone had no effect in vitro. In vivo dexamethasone administration resulted in elevated serum rT3 concentrations after 1 day, and after 5 days, in inhibition of T4 to T3 conversion and rT3 degradation without altering serum T4, T3, or thyrotropin concentrations. Endotoxin treatment had no effect of iodothyronine metabolism in liver homogenates. In kidney homogenates the reaction rates and response to propylthiouracil in vitro were similar to