In systemic nonthyroidal illness (NTI), peripheral production of T3 from T4 is decreased, resulting in a decreased serum T3 concentration. We investigated whether factors in serum of NTI patients may play a role in this energy-saving adaptation mechanism. Metabolism of T4 and T3 by rat hepatocytes in primary culture was measured in the presence of 10% serum of normal subjects or of patients with NTI and related to the severity of disease. Patients with NTI were grouped according to serum thyroid hormone abnormalities: group I, serum rT3, T3, and T4 normal; group III, rT3 elevated, T3 decreased, T4 normal; group IV, rT3 elevated, T3 and T4 decreased. Compared with metabolism in the presence of normal serum, metabolism of T4 and to a lesser extent of T3 was progressively decreased in the presence of serum of patients of groups I-IV. A decreased net deiodination of T4 and T3 (corrected for differences in free hormone concentration) without an increase in conjugated T4 and T3 (corrected for differences in free hormone concentration) was observed, similar to results in experiments with compounds inhibiting transport into the cells and not the metabolic processes (5' deiodination) per se. Deiodination of T4 in vitro was correlated with serum T3 concentration of the patient (r = 0.69). Serum of patients with NTI influences thyroid hormone handling by hepatocytes comparable to the effect of transport inhibitors and not to that of the 5'-deiodinase inhibitor propylthiouracil, suggesting that decreased thyroid hormone transport over the cell membrane may play a role in lowered T3 production in NTI.
Thyroid hormone uptake into cultured human hepatocytes was studied using measurement of cell-associated radioactivity of radioiodinated thyroid hormones after 10-min incubation in culture medium with 0.5% BSA. Furthermore, 20-h incubations were performed to study transport and further intracellular metabolism. The results indicate the presence of saturable active uptake systems for T4, T3, and rT3, as addition of the unlabeled hormone (1, 5, and 2 mumol/L, respectively) to the medium resulted in a decrease in cell-associated radioactivity of 20-30%. Inhibition was also achieved after 30-min preincubation with fructose (10 mmol/L), which induces a decrease in intracellular ATP or ouabain (0.5 mmol/L), indicating energy dependence and the necessity for a sodium gradient for at least part of the transport process, respectively. After 20-h incubation, iodide production was inhibited in the presence of ouabain (0.5 mmol/L), propylthiouracil (100 mumol/L), or a monoclonal antibody (81-1A1-10; ascites dilution, 1:200) directed against thyroid hormone transport systems in rat hepatocytes. These data indicate that there is a high degree of similarity between the properties of the uptake process and subsequent conversion of thyroid hormones in human and rat hepatocytes, although the rates of uptake and conversion are lower in human hepatocytes. Furthermore, regulation of thyroid hormone uptake at the level of the plasma membrane may also be operative in human hepatocytes.
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