Type 1 deiodinase is stimulated by iodothyronines and involved in thyroid hormone metabolism in human somatomammotroph GX cells

Abstract

Background: Local 5 0 -deiodination of L-thyroxine (T 4 ) to the active thyroid hormone, 3,3 0 ,5-tri-iodothyronine (T 3 ) via two deiodinase isoenzymes (D1 and D2) has an important role for various T 3 -dependent functions in the anterior pituitary. However, no evidence has been presented yet for thyroid hormone inactivation via the 5-deiodinase (D3) in anterior pituitary models. Methods: Using the human somatomammotroph cell line, GX, we analysed effects of T 3 and its 5 0 -deiodination product, 3,5-di-iodothyronine (3,5-T 2 ), on deiodinase activities, measuring release of iodide-125 ( 125 I ¹ ) from phenolic-ring-or tyrosyl-ring-labelled substrates respectively. Results: T 3 and 3,5-T 2 rapidly stimulated D1 activity in GX cells in the presence of serum in the culture medium, whereas D2 activity was not detectable under these conditions. However, when the cells were kept under serum-free conditions, specific activity of D2 reached levels similar to those of D1. With tyrosyl-ring labelled 3,5-[125 I]-,3 0 -T 3 as substrate, a significant release of 125 I ¹ was observed in GX cell homogenates. This is comparable to the D1 activity of liver membranes, which preferentially catalyses 5 0 -deiodination, but to some extent also 5-deiodination, at the tyrosyl ring. Conclusions: D1 activity of human GX cells is increased by T 3 and 3,5-T 2 . Inactivation of T 3 in the anterior pituitary might occur by deiodination at the tyrosyl ring via D1, thus terminating the stimulatory thyroid hormone signal in human somatomammotroph cells.

Dysregulation of iodothyronine deiodinase enzyme expression and function in human pituitary tumours

“…Although D3 activity has been described previously in the pituitary (Tanaka et al ., 1992; Calvo et al ., 1998), D1 has been attributed with the main ‘inactivating’ role in the pituitary through its ability to deiodinate at the 5‐position (Baur et al ., 1997; Baur & Kohrle, 1999). However, our data suggest that D1 mRNA is expressed at low levels (and is undetectable in approximately 50%) in both normal and tumourous pituitaries.…”

“…D1 is thus important for generating plasma concentrations of biologically active T3 through its actions in liver, kidney, and thyroid. D1 has previously been identified in rat pituitary GH3 (prolactin‐secreting) cells (Kohrle et al ., 1995) and in human somatomammotroph GX cells (Baur & Kohrle, 1999). Type 2 deiodinase (D2) deiodinates T4, and with lower affinity rT3, specifically at the phenolic ring in the 5′ position.…”

“…The type 3 iodothyronine deiodinase (D3) removes iodine from the 5‐position of the tyrosyl ring and thus catalyses the inactivation of biologically active T 3 to di‐iodothyronine (T 2 ) and T 4 to inactive rT 3 . D3 has not been detected previously in pituitary cell lines derived from either rat or human anterior pituitary (Baur et al ., 1997; Baur & Kohrle, 1999), although D3 activity has been detected in the rat posterior pituitary (Tanaka et al ., 1992). Despite their clear importance, the critical role of deiodinase enzymes as determinants of local ligand supply, and therefore thyroid hormone action in the pituitary, remains largely unexplored.…”

Role of Iodine, Selenium and Other Micronutrients in Thyroid Function and Disorders

“…The substrate and/or products of the enzyme (T 4 , T 3 ) induce its expression. D1 activity, in fact, is stimulated in hyperthyroidism and decreased in hypothyroidism in most [138,139,[146][147][148][149][150][151][152]. Fasting decreases and carbohydrate feeding stimulates hepatic D1 activity.…”

Expressão das iodotironinas desiodases nas neoplasias tireoidianas

“…Estudos prévios não identificaram a expressão da D3 em linhagem celular derivada da hipófise anterior humana (84). No entanto, a análise de adenomas hipofisários demonstrou níveis de RNA mensageiro aproximadamente 7 vezes mais elevados do que no tecido hipofisário normal.…”