Extrathyroidal conversion of thyroxine to triiodothyronine in sheep.

A study of in vivo extrathyroidal conversion of thyroxine (T4) to triiodothyronine (T3) has been conducted in sheep using a newly developed radioimmunoassay for serum T3 and a protein-binding assay for serum T4. Serial measurement of serum T3 concentration were conducted after administration of 4 mg Na-1-thyroxine iv to four euthyroid sheep. The serum T3 concentrations during these studies increased 3 to 7 times within 15 hours and the T3/T4 concentration ratios peaked between 39 and 48 hours at values of 0.003-O.011. The initial T4 levels exceeded 40 M-g/100 ml so that endogenous TSH secretion presumably was inhibited maximally. And since T3 contamination of the injected T4 did not exceed 0.1%, the data suggest that significant extrathyroidal conversion of T4 to T3 occurs in sheep. This conclusion is further supported by a chronic T4 injection study in a thyroidectomized sheep where endogenous T3 secretion was absent and the serum T3 concentrations averaged 0.78% of the T4 level. In three additional sheep m I -T4 and I-T3 kinetic studies were conducted to measure T4 and T3 turnover. The mean volumes of distribution of T4 and T3 were 9.5 and 20 1, the mean t1/2 values 1.36 days and 5.5 hr, the mean serum concentrations 6.0 M-g/100 ml and 55 ng/100 ml, and mean turnover values 291 and 32 fig/day, respectively. Calculated steady state fractional T4 to T3 conversion in the chronic injection experiment was 0.097 and calculated absolute T4 to T3 conversion 29 Hg/day. Thus about 91% of daily T3 turnover in sheep appears to be derived peripherally from monodeiodination of T4 {Endocrinology 91: 1141, 1972) T T IS NOW well-established that thyroxine ^ is converted to triiodothyronine in peripheral tissues of man (1-4) and rats (5). Previous studies from our laboratories did not provide evidence for an extrathyroidal origin of circulating triiodothyronine (T3) in the sheep (6). However, these data were derived by column chromatographic techniques which involve procedural monodeiodination of thyroxine (T4) to T3 (6,7), such that a relatively large correction for in vitro artifact was necessary. Thus, small concentrations of endogenous labeled T3 derived from administered labeled T4 might not have been detected. Using a sensitive radioimmunoassay for T3 (8,9) we have reinvestigated the problem of T4 to T3 conversion in adult sheep. In addition, T4 and T3 kinetic studies were conducted so that T4 to T3 conversion could be quantified in relation to total thyroid hormone turnover. Received September 29, 1970. Supported by United States Public Health Service Grant Numbers AM-O427O, AM-13126 and AM16155 from the National Institutes of Arthritis and Metabolic Diseases and the John A. Hartford Foundation, Inc. * Recipient of NIH Career Development Award K04 AM-70 225. Materials and Methods Four healthy adult ewes (Columbia or ColumbiaSuffolk cross) maintained on baled alfalfa were studied. Four mg Na-1-thyroxine (Flint Laboratories lot #V61RS) was injected intravenously and serial blood samples collected over a period of about 96 hours for measurements of serum T3 and T4 concentrations. The T3 contamination of this lot of T4 was assessed as described previously (10) using a specific T3 antiserum kindly supplied by Dr. W. E. Mayberry. One hundred eighty (180) ng of this T4 produced the same displacement of labeled T3 from antibody as did 0.18 ng T3 so that the extent of apparent T3 contamination was 0.1%. Whether this represents T4 cross-reaction or T3 contamination is not known; however T3 contamination could not have exceeded 0.1%. In one additional animal, iv Na-1-thyroxine was administered daily for a 10-day period beginning 48 hours after thyroidectomy. The initial T4 dose was 2 mg; this was followed by a daily 1 mg dose for 10 days. Blood samples were collected before and 48 hours after thyroidectomy, twice daily (before and 6 hr after each T4 injection) on days 5 to 8, and daily thereafter (before each injection) through day 11. Serum T4 and T3 concentrations were measured in all samples. Finally in three additional ewes, T4 and T3 kinetic studies were conducted to measure hormone turnover. Indwelling jugular vein catheters were introduced to facilitate isotope administration and blood collections. A 600-mg dose of potassium perchlorate