In the past, investigators have used thyroxine labeled either with JIP" in the 3',5'-position or with C14 in the carboxyl position to study the metabolism of thyroxine in vivo. Although these studies have yielded much valuable information, our knowledge about the metabolic fate of the ring structure in thyroxine is incomplete because both the 3'5'-IJ13 and the carboxyl-C14 are rapidly removed from thyroxine in vivo by deiodination and .decarboxylation. To investigate the metabolic fate of the thyroxine nucleus, L-thyroxine-C14 labeled uniformly in the phenolic ring has been synthesized in our laboratory. Studies on the metabolism of ring-labeled L-thyroxine-C14 following iv administration to rats, dogs, and human subjects are reported in this communication.
METHODS AND MATERIALSSynthesis of ring-labeled L-thyroxine-C"4.1 The L-thyroxine-C1' labeled in the phenolic ring was prepared from uniformly labeled phenol-C14 in 2.6% over-all yield in the following manner: phenol-C1' was converted to 4-methoxyphenol-C1' by a series of reactions that included the formation of phenylbenzene sulfonate, nitration to the 4-nitro ester, saponification to 4-nitrophenol, methylation to the ether, reduction of the nitro group to 4-methoxyaniline, diazotization of the amino group, and finally hydrolysis of the diazonium salt. The conversion of 4-methoxyphenol-C1' to L-thyroxine-C1' was accomplished by modification of a route developed by Chalmers, Dickson, Elks, and Hems (1) The L-thyroxine-C1' possessed the following physical L-Thyroxine (3',5'-PJ1f). The L-thyroxine-13 used in these experiments was labeled in the 3',5'-positions and was obtained commercially.3 It was demonstrated to be radioactively homogeneous by paper chromatography before use. Experimental subjects. The metabolism of L-thyroxine-C14 was investigated in three intact dogs, three intact rats, and nine rats with their common bile ducts cannulated. With the information obtained from these animal experiments, permission was obtained from the Atomic Energy Commission to study the metabolism of L-thyroxine-C1' in two patients with inoperable carcinoma.For the balance experiments, in which an attempt was made to account for all of the administered radioactivity, rats were kept in gas-tight, all-glass metabolic cages for the separate collection of urine, feces, and expired CO2. The amount of radioactivity in the expired CO2 was measured quantitatively by a modification of the method of Fredrickson and Ono (5). Comparable balance experiments could not be carried out in man and dog because the specific activity of the L-thyroxine-C1' was not high enough to permit accurate measurement of radioactivity in the large quantity of feces and CO2 produced by these species.The dogs were kept in metabolic cages to allow for the collection of urine and feces separately. The human subjects were housed on the metabolic ward for the entire experimental period.Between 3 Asg (.0046 ptc) and 116 lg (0.180 4Ac) of ringlabeled L-thyroxine-C' dissolved in 0.2 ml of rat serum was administere...