The Calorigenic Action of D- And L-Thyroxin

Abstract

Evaluation of the significance of calorigenic responses obtained by the assay of constituents of the thyroid in myxedematous persons is fraught with difficulty. The questions of absorption, excretion and destruction of the material administered all intrude to plague the investigator. The role of physical properties such as solubility or optical activity must be identified. The possibility of enhancement of physiologic potency brought about by alteration in physical state has been mentioned in previous communications (1) (2). In the first paper of this series (1) it was shown that racemic crystalline thyroxin and optically active thyroxin polypeptide had equal calorigenic activity when given in equal iodine dosage.To settle, if possible, the single point of the part played by optical activity the present study was undertaken. We are indebted to Professor C. R. Harington for a supply of pure crystalline d-and l-thyroxin (3). The substances have been assayed on myxedema patients .in the manner described in earlier papers (1) (2). The results are shown graphically in Figure 1. A curve which represents the average response obtained in five myxedema patients receiving 1.0 mgm. of thyroxin polypeptide (50 per cent iodine) per day by mouth is also included in this figure in order to indicate the standard response to 0.5 mgm. of thyroid iodine daily.Special care was taken to avoid racemization of the optically active material. The weighed microcrystalline powder was dissolved in cold 0.01 normal sodium hydroxide, of which 6 cc. were used per milligram of iodine. Three cubic centimeters of the freshly prepared thyroxin solution were measured into sterile ampoules. To each ampoule was added 1 cc. of distilled water and enough fifth-normal orthophosphoric acid to bring the reaction of the solution to pH 6.5. The ampoules were then stoppered with special "bacteriological " rubber caps, shaken to disperse the precipitated thyroxin, and heated at 800 C. for ten minutes. They were then kept iced until used. Three or four such ampoules were prepared at once, to be used on successive days. Immediately before injection, one-half cubic centimeter of cold tenth-normal sodium hydroxide was added by means of a sterile syringe and the thyroxin again dissolved by shaking.

The Effect of Heating With Alkali on the Calorigenic Activity of Desiccated Thyroid and of Thyroxine 1

“…However, too few data are presented to warrant quantitative deductions. Salter, Lerman and Means (14), using material obtained by Harington (15) in the same manner as that supplied to Gaddum, reported the two isomers to possess the same activity in man.…”

Comparative Calorigenic Action of Normal and Patho-Logical Thyroid Glands Administered in Equi-Thyroxine Doses

“…Activity two times as great was actually found, a result that only approximates the expected value. In this connection, it should be mentioned that Salter, Lerman and Means (20) found no difference in the calorigenic activity of the d-and 1-forms of thyroxine when administered to patients with spontaneous myxedema.…”

Measurement of Thyroid Activity by the Mouse Anoxia Method

“…By the subcutaneous route we found the L-isomer to be twice as active as the DL-mixture (Table VI) and closely similar results were obtained from oral administration, in accord with the findings of Foster, Palmer, and Leland (1936) and of Reineke andTurner (1943 and1945). The results suggest that the D-isomer is inactive, but it would be unwise, in view of the large experimental errors involved, to draw final conclusions from these results, especially as a number of workers have found D-thyroxine active in man (Salter, Lerman, and Means, 1935;Pitt Rivers and Lerman, 1948). We have not yet been able to examine the pure D-isomer by this method.…”