Evidence for an inhibitor of extrathyroidal conversion of thyroxine to 3, 5, 3′-triiodothyronine in sera of patients with nonthyroidal illnesses
Journal
Journal of Clinical Endocrinology and Metabolism
Journal Volume
60
Journal Issue
4
Pages
666-672
Date Issued
1985
Author(s)
Abstract
To determine whether an inhibitor of extrathy-roidal conversion(IEC) of T4to T3 ispresent in sera of patients with nonthyroidal illness (NTI), we incubated ratliver homogenate (∼4mg protein) with T4 (2.5 μM) and dithiothreitol (5 DIM) in the presence of evaporated diethyl ether extracts of (normal or NTI sera. The T3 producedwas quantified by RIA. Extracts of NTI sera caused dose-dependent inhibition in the (conversion ofT4 to T3. T3 produced in the presence of 20 NTI sera (1.0 mleqaliquots) was 76 ± 5.5% (mean ± SE; range, 18–116) that of normal sera (100 ± 4.1% n = 10; P ¼ 0.01); it was more than 2 SD below the normal mean ineight patients. Inhibition of T3 production by NTI sera was correlated highlysignificantly with the activity of a thyroid hormone-binding inhibitor (THBI) also present in ether extracts of these sera (r = 0.82; n = 20; P ¼ 0.001). Since THBI may be a lipid, we studied the effect of lipids on hepatic (conversion of T4 to T3. Several fatty acids were potent inhibitors of the conversion in vitro. Doses (in micromoles) causing50%inhibition in different experiments varied between 0.2–0.52 for arachidonic acid,0.3–0.56 for linolenic acid, 0.38–0.40 for linoleic acid, and 0.8–0.9 for oleic acid.Other lipids had less or no inhibitory activity. The inhibition of hepatic T4 5'-monodeiodination by arachidonic acid was competitive in nature (Ki, ∼0.11 mM). Pretreatment of ratliver with phospholipase A2 for 10–60 min led to a progressive reduction in the conversion of T4 toT3 Moreover, the evaporated ether extract{(of phospholipase A2-treated rat liver homogenate reduced T4 toT3conversion by untreated rat liver homogenate. There was a significant correlation between serum concentrations of free fatty acids andIEC activity in NTI sera (r = 0.74; n = 10; P ¼¼ 0.02). The various data suggest that 1) many NTI sera contain a potent IEC; 2) somefatty acids are potent IECs; 3) like THBI, IEC may be a lipid moiety; and 4) activation of tissue phospholipases may contribute importantly to reduced extrathyroidal T3 production in NTI,presumably by releasing inhibitory fatty acids that act locally first and more generally after their release into the circulation.
SDGs
Type
journal article