THE METABOLISM OF I 131 -LABELED THYROXINE, TRIIODOTHYRONINE AND DIIODOTYROSINE BY ANISOLATED PERFUSED RABBIT LIVER 1

465

167

A B S T R A C T Studies of the possibility that thyroxine (T4) is converted to 3,5,3'-triiodo-L-thyronine (T3) in the extrathyroidal tissues in man have been conducted in 13 patients, all but two of whom were athyreotic or hypothyroid, and all of whom were receiving at least physiological replacement doses of synthetic sodium-Lthyroxine.T3 was found in the sera of all patients, in concentrations ranging between 243 and 680 ng/100 ml (normal range 170-270 ng/100 ml). These concentrations were far in excess of those which would have been expected on the basis of the T3 contamination of the administered T4, as measured by the same technique employed in the analysis of serum. When oral medication was enriched with 'I-labeled T4 for 8 or more days, labeled T3 and tetraiodothyroacetic acid (Tetrac or TA4) were found in the serum to the extent of approximately 2-5% of total radioactivity, as assessed by unidimensional paper chromatography. The same results were obtained with a specially purified lot of radioactive T4 containing less than 0.1% T3 as a contaminant. The identities of the 'I-labeled T3 and TA4 were verified by two-dimensional chromatography as well as by specific patterns of binding in serum. The labeled T3 isolated was bound by albumin and by T4-binding globulin (TBG), but not by T4-binding prealbumin (TBPA); in contrast the labeled TA4 was bound by albumin and TBPA, but not by TBG.To exclude the possibility that the conversion of T4 to T3 was a peculiarity of the oral route of administra- There is no doubt whatsoever that at least a portion of the T3 in the blood results from direct secretion by the thyroid gland, T3 having been found in the thyroid venous effluent, and in concentrations substantially higher than in the concurrently sampled arterial blood (4, 5). What has remained uncertain, however, is what fraction, if any, of the T3 in the blood arises from the

Section: Discussionmentioning

confidence: 99%

Conversion of Thyroxine (T4) to triiodothyronine (T3) in athyreotic human subjects

Braverman¹,

Ingbar²,

Sterling³

1970

465

167

“…However, a cause and effect relationship may be postulated between liver injury and abnormal T4 and Ts metabolism. In in vitro experimentation, perfused liver and liver tissue culture were shown to convert T4 to Ts (7,13). Reduced serum Ts values (21,22) were associated with liver cirrhosis and alcoholic hepatitis.…”

Section: Discussionmentioning

confidence: 99%

“…The contribution of this pathway to the total Ts production appears to be higher in man and sheep than in rat. T3 can also be converted from T4 in vitro by perfused rabbit liver (7) and rat heart (8), by slices of pituitary (9), kidney (10), and brain (11), and by tissue cultures of human fibroblast (12), kidney, and liver (13). Still, it is not known in what proportion the different organs contribute to the overall T3 production in the intact animal under physiological circumstances.…”

Section: Introductionmentioning

confidence: 99%

Reduced peripheral conversion of thyroxine to triiodothyronine in patients with hepatic cirrhosis.

Nomura¹,

Pittman²,

Chambers³

et al. 1975

209

A B S T R A C T The role of liver in the peripheral conversion of thyroxine (T4) to triiodothyronine (Ts) was studied in normal subjects and patients with alcoholic liver disease by measurement of thyrotrophin (TSH) and total and free T4 and T3 in random and serial serum samples. Also, T4 to Ts conversion rates and Ts disposal rates were compared by noncompartmental analysis. While the mean total serum T4 values were similar for the two groups, 8.6 and 8.1 ug/dl, the mean free To value was significantly higher in the cirrhotic patients (3.3 ng/dl) than in the normal subjects (2.1 ng/dl, P < 0.001). The mean serum T3 value, 85 ng/dl, was significantly reduced in the hepatic patients as compared to a mean serum T8 value of 126 ng/dl in the normal subjects (P < 0.001), while the free T3 value was 0.28 ng/dl in both groups. The reduction of the serum total and free Ts values were closely correlated with the degree of liver damage, as indicated by elevation of serum bilirubin (r = -0.547) and reduction of serum albumin (r = 0.471). The mean serum TSH level was 3.1 AiU/ml in the normals and 7.1 tU/ ml in the cirrhotic patients (P < 0.001). 15% of the hepatic patients had serum TSH values above 10 AU/ ml, which, however, did not correlate with any of the four liver function tests studied. Serial blood sampling from two convalescing patients with alcoholic hepatitis showed a gradual normalization of serum TSH and Ts levels as the liver function improved. After oral T4 administration, 0.25 mg/day for 10 days, three of four cirrhotic patients studied failed to raise their serum Ts values. The mean T4 to Ts conversion rate of seven normal subjects was 35.7%. The mean T4 to T3 conversion rate of four cirrhotic patients studied was significantly reduced to 15.6% (P < 0.001). The mean Received for publication 12 March 1974 and in revised form 22 May 1975. disposal rates of T4 and T3 of the normal subjects were 114 and 34 ,ig/day, respectively. The ratio of T, disposal to T3 disposal was 3.5. In contrast, the mean T4 disposal rate, 82 Ag/day, and the mean Ts disposal rate, 10 ug/day, were both reduced in the cirrhotic patients. Their ratio of T4 disposal to Ts disposal was 7.9. These findings suggest that impairment of T4 conversion in patients with advanced hepatic cirrhosis may lead to reduced Ts production and lowered serum Ts level. Therefore, the liver is one of the major sites of T4 conversion to Ts.

“…Many tissues are known to deiodinate thyroxine (T4)l with the resultant production of 3,5,3'-triiodothyroxine (T3) (1)(2)(3)(4)(5)(6)(7)(8)(9), but only recently has it been appreciated that most ofthe circulating T3 is derived from extrathyroidal 5'-monodeiodination of T4 rather than from thyroidal secretion (10)(11)(12)(13). This deiodination increases the metabolic effect of T4 because T3 is more potent than T4.…”

Section: Introductionmentioning

confidence: 99%

Regulation of the Conversion of Thyroxine to Triiodothyronine in the Perfused Rat Liver

Jennings¹,

Ferguson²,

Utiger³

1979

100

A B S T R A C T This study was undertaken to de-termine what factors control the conversion of thyroxine (T4) to triiodothyronine (T3) in rat liver under conditions approximating those found in vivo. Conversion of T4 to T3 was studied in the isolated perfused rat liver, a preparation in which the cellular and structural integrity is maintained and that can perform most of the physiologic functions of the liver. The perfused liver readily extracted T4 from perfusion medium and converted it to T3. Production of T3 by the perfused liver was a function of the size of the liver, the uptake of T4 by the liver, and the presence of T4-5'-deiodinase activity. Production of T3 was increased by increasing the uptake of T4 by liver, which could be accomplished by increasing the liver size, by increasing the perfusate T4 concentration, or by decreasing the perfusate albumin concentration. These changes occurred without altering the conversion of T4 to T3. The liver had a large capacity for extracting T4 and for T4-5'-deiodination to T3, which was not saturated at a T4 concentration of 60 ,ug/dl. Production of T3 was decreased by inhibiting hepatic T4-5'-deiodinase with propylthiouracil, which decreased T3 production by decreasing the conversion of T4 to T3. Propylthiouracil did not alter hepatic T4 uptake.Fasting resulted in a progressive decrease in hepatic T4 uptake to 42% of control levels by the 3rd d of fasting; this was accompanied by a proportionate decrease in T3 production. The rate of conversion of T4 to T3 did not change during fasting. When T4 uptake in 2-d-fasted rat livers was raised to levels found in fed rats by increasing the perfusate T4 concentration from 10 to 30 ,g/dl, T3 production retumed to normal. Again, no change in the rate of conversion of T4 to T3 was observed.Presented in part at the Annual Meeting of The American Society for Clinical Investigation, Washington, D. C., 6 May 1979(1979 1614These results indicate that the decreased hepatic T3 production during fasting primarily results from decreased hepatic uptake of T4, rather than from changes in T4-5'-deiodinase activity. Thus, these studies have delineated a new mechanism that functions independently of enzyme quantity or activity whereby production of T3 from T4 is regulated.