Guadalupe N. Chua Teco

Serum thyroid hormone binding inhibitor in nonthyroidal illnesses

We have employed the recently developed competitive ligand binding assay (CLBA) to study thyroid hormone binding inhibitor (THBI) in ether extracts of sera of 25 patients admitted to the Medical Intensive Care Unit with a variety of nonthyroidal illnesses (NTI). THBI was detected in 60% (15/25) of patients using one sample/patient and in 88% (15/17) using multiple (two to six) samples from different days. Mortality rate and mean serum concentrations of total T4, total T3, and albumin were similar in THBI-positive and THBI-negative patients. There was a tendency for a higher frequency of low serum total T4 in THBI-positive (10/15) than in THBI-negative (3/10) patients but the difference was not statistically significant (P less than 0.1 by Chi square). However, the mean dialyzable fraction of T4 (DFT4 0.11 +/- 0.02%, n = 9 v 0.054 +/- 0.004%, n = 10) and DFT3 (0.54 +/- 0.05% v 0.40 +/- 0.032%) were both significantly (P less than 0.05) higher in THBI-positive patients than THBI-negative patients. There was a significant correlation between THBI and DFT4 (r = 0.55, P less than 0.02) or DFT3 (r = 0.54, P less than 0.02). Prior extraction of serum with ether reduced DFT4 in NTI patients with high baseline DFT4 but not in normal subjects or NTI patients with mildly abnormal baseline DFT4. Addition to a normal serum (0.1 mL) of evaporated ether extract of a pooled NTI serum (0.10- to 3.0-mL equivalent) increased DFT4 progressively from 0.025% to 0.14%. Similar extract of a pooled serum of normal subjects had little or no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolism of 3,5,3'-triiodothyronine sulfate by tissues of the fetal rat: a consideration of the role of desulfation of 3,5,3'-triiodothyronine sulfate as a source of T3

ABSTRACTS: We have recently demonstrated that serum concentration of 3,5,3‘-triiodothyronine sulfate (T3S) is markedly elevated in the human newborn at a time when serum 3,5,3’-triiodothyronine (T3) is very low. The present study explores the ability of maternal (19–21 d pregnant) and near-term fetal Sprague-Dawley rat tissues to 1) monodeiodinate T3S and T3 in both the outer and the inner ring and 2) desulfate T3S to T3. Maternal liver microsomes metabolized T3S exceedingly efficiently (compare fetus p < 0.05). Eighty percent or more of T3S was consumed during its incubation with 360 μg/mL microsomes for 2 h. The majority of the consumption of T3S by adult liver microsomes occurred by its 5‘-monodeiodination to 1; little inner-ring monodeiodination to 3,3’-diiodothyronine was demonstrable. In fetal liver microsomes, however, over 75% of the substrate T3S remained unchanged after a 2-h incubation. T3 was metabolized similarly moderately by fetal and maternzl liver microsomes. Brain microsomes metabolized T3S poorly in both the mother and the fetus. Over 90% of substrate T3S remaned unchanged after a 2-h incubation in each case. Interestingly, brain microsomes metabolized T3 more rapidly than T3S (p < 0.05). In the fetus, desulfation of T3S to T3 was clearly evident only in microsoms from the liver and the brain; in the adult, it was plentiful in many tissues. Fetal liver and brain tissues metabolize T3S poorly, and both actively desulfate T3S to T3. These data and those indicating high serum T3S in the fetus suggest that T3S is a local source of T3 in critical tissues in the fetus and possibly in adults with the low T3 syndrome.

Thyroxine Inner Ring Monodeiodinating Activity in Fetal Tissues of the Rat

ABSTRACT: We studied thyroxine (T4) inner ring monodeiodinating activity (5-MA) in various tissues of fetal, maternal, and adult male rats. Tissue homogenates were incubated with 0.26 μM T4 in 0.1 M phosphate buffer (pH 7.4) containing 10 mM EDTA and 400 mM dithiothreitol (final volume 0.7 ml) for 10 min at 37° C; the 3,3‘,5’-triiodothyronine (rT3) generated was measured by radio-immunoassay of ethanol extracts of incubation mixture and the result was corrected for rT3 degradation during incubation. Compared to maternal tissues, T4 to rT3 5-MA in the 14-day-old fetus was increased about 70 times in skeletal muscle (mean ± SEM, velocity, 5.4 ± 0.9 versus 0.08 ± 0.01, pmol rT3/h/mg protein); ∼8 times in intestine (0.72 ± 0.17 versus 0.09 ± 0.03); and ∼4 times in cerebral cortex (19 ± 0.5 versus 4.5 ± 0.9), while it was similar in skin (3.2 ± 0.48 versus 2.6 ± 0.52). Hepatic T4 5-MA approximated 1.1 ± 0.63 in the 14-day-old fetus; it could not be measured reliably in maternal or 19-day fetal tissue because of extensive (>90%) degradation of rT3 during incubation. Relative to mother, T4 5-MA in 19-day fetal tissues was increased ∼30-fold in intestine, ∼20-fold in skeletal muscle, and ∼6-fold in cerebral cortex while it was similar in skin. The T4 5-MA in maternal rat tissues did not differ significantly from corresponding values in adult male rat, except skin, where it was lower in the mother rat (2.6 ± 0.52 versus 4.6 ± 0.61, p < 0.05). In summary, relative to adult tissues T4 5-MA is exceedingly active in several fetal tissues, most notably in skeletal muscle followed by intestine and cerebral cortex.

Inhibition of nuclear T3 binding by fatty acids

Studies were performed to evaluate a possible modulatory role of lipids on the binding of T3 to rat liver nuclear receptors in vitro. Unsaturated fatty acids were potent inhibitors of the binding of [125I] T3 to isolated rat liver nuclei. Doses (in mumol/L) causing a 50% inhibition of nuclear T3 binding were 10 for palmitoleic acid, 11 for linoleic acid, 22 for oleic acid, 24 for arachidonic acid, and 37 for linolenic acid. Other lipids had less or no inhibitory activity. Unsaturated fatty acids reduced the affinity constant (Ka) of the binding of T3 to nuclear receptors to 57.4% +/- 11.0% that of controls (mean +/- SE 1.04 +/- 0.14 v 1.97 +/- 0.23 10(9) L/M, n = 5; P less than .02) but did not affect the maximal binding capacity (MBC) (1.47 +/- 0.20 v 1.55 +/- 0.10 10(-10) M/L; NS). Evaporated ether extracts of rat liver homogenate pretreated with phospholipase A2 for five to 20 minutes (that liberates unsaturated fatty acids from phospholipids) demonstrated a progressive inhibition of nuclear T3 binding with time when compared with ether extracts of untreated rat liver homogenate (F = 16.1; P less than .01). Evaporated, fatty-acid-rich ether extracts of human sera caused a dose-dependent inhibition in the binding of [125I] T3 to nuclear T3 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in Thyroid Function Parameters Following Administration of Fatty Acids

Recent studies suggest that a thyroid hormone binding inhibitor (THBI) is detected frequently in sera of patients with systemic non-thyroidal illness (NTI) (1–3). There is at present a paucity of information concerning the role of THBI in thyroid hormone abnormalities observed commonly in NTI. THBI appears to be a lipid moiety and unsaturated fatty acids are promising candidate THBIs (1). Serum concentrations of some unsaturated fatty acids (e.g., oleic acid) are markedly increased in NTI (4). In this study, we have examined the effect of the parenteral administration of unsaturated fatty acids on serum thyroid hormone and TSH concentrations in the rat.