Ontogeny of Iodothyronine Deiodinases in Human Liver1

Abstract

The role of the deiodinases D1, D2, and D3 in the tissue-specific and time-dependent regulation of thyroid hormone bioactivity during fetal development has been investigated in animals but little is known about the ontogeny of these enzymes in humans. We analyzed D1, D2, and D3 activities in liver microsomes from 10 fetuses of 15-20 weeks gestation and from 8 apparently healthy adult tissue transplant donors, and in liver homogenates from 2 fetuses (20 weeks gestation), 5 preterm infants (27-32 weeks gestation), and 13 term infants who survived up to 39 weeks postnatally. D1 activity was determined using 1 M [3Ј, 5Ј-125 I]rT 3 as substrate and 10 mM dithiothreitol (DTT) as cofactor, D2 activity using 1 nM [3Ј, 5Ј-125 I]T 4 and 25 mM DTT in the presence of 1 mM 6-propyl-2-thiouracil (to block D1 activity) and 1 M T 3 (to block D3 activity), and D3 activity using 10 nM [3, I]T 3 and 50 mM DTT, by quantitation of the release of 125 I Ϫ . The assays were validated by high performance liquid chromatography of the products, and kinetic analysis [Michaelis-Menten constant (K m ) of rT 3 for D1: 0.5 M; K m of T 3 for D3: 2 nM]. In liver homogenates, D1 activity was not correlated with age, whereas D3 activity showed a strong negative correlation with age (r Ϫ0.84), with high D3 activities in preterm infants and (except in 1 infant of 35 weeks) absent D3 activity in full-term infants. In microsomes, D1 activities amounted to 4.3-60 pmol/min/mg protein in fetal livers and to 170 -313 pmol/min/mg protein in adult livers, whereas microsomal D3 activities were 0.15-1.45 pmol/min/mg protein in fetuses and Ͻ0.1 pmol/min/mg protein in all but one adult. In the latter sample, D3 activity amounted to 0.36 pmol/min/mg protein. D2 activity was negligible in both fetal and adult livers. These findings indicate high D1 and D3 activities in fetal human liver, and high D1 and mostly absent D3 activities in adult human liver. Therefore, the low serum T 3 levels in the human fetus appear to be caused by high hepatic (and placental) D3 activity rather than caused by low hepatic D1 activity. The occasional expression of D3 in adult human liver is intriguing and deserves further investigation. (J Clin Endocrinol Metab 83: 2868 -2874, 1998 T HE bioactivity of thyroid hormone is regulated importantly by enzymatic deiodination in peripheral tissues (1-4). The prohormone T 4 is converted by outer ring deiodination (ORD) to the active hormone T 3 . Both T 4 and T 3 are inactivated by inner ring deiodination (IRD) to rT 3 and 3,3Ј-diiodothyronine (3,3Ј-T 2 ), respectively. The latter metabolite is also produced by ORD of rT 3 . The three iodothyronine deiodinases involved in these processes have been characterized as homologous transmembrane selenoproteins that require thiols as cofactor (1-4). The type I deiodinase (D1) has both ORD and IRD activity. It is located in liver, kidney, and thyroid and is important for plasma T 3 production. rT 3 is the preferred substrate for D1, although the deiodination of other iodothyronines is greatly a...

Reduced expression of thyroid hormone receptor β in human nonalcoholic steatohepatitis

“…As expected, we could not detect SLCO1C1 , DIO2 and DIO3 transcripts. DIO3 has been described in human fetal liver and adult livers of critically ill patients, but in line with our findings, it was reported to be absent in healthy adult human liver samples (26, 27). We identified hepatic expression of both TH receptor genes, which was not correlated to serum TSH, corroborating previous findings (28).…”

Fetal Tissues Are Exposed to Biologically Relevant Free Thyroxine Concentrations during Early Phases of Development

“…The low concentrations in fetal fluids of T 3 , the high concentrations of rT 3 , and the high molar rT 3 /T 4 ratios suggest that iodothyronines transferred from maternal to fetal fluids in early pregnancy undergo the same inactivating processes that are characteristic of later fetal development (27)(28)(29)(30)(31)(32)(33)(34)(35)(36). These are attributed to high activities of inner ring 5Ј-iodothyronine deiodinase (D-III), an inner ring deiodinating isoenzyme with preference for T 3 over T 4 as substrate, and of sulfo-transferases, producing T 4 and T 3 sulfates.…”

Current concepts and challenges to unravel the role of iodothyronine deiodinases in human neoplasias

“…When evaluating liver microsomes, high DIO1 and DIO3 activities are detected in fetal liver but only DIO1 and mostly none DIO3 activities are found in adult liver. DIO2 activity is virtually absent in both fetal and adult tissues (Richard et al 1998). Both human hepatocytes as well as human hepatoblastoma-derived cells HepG2 show an approximately ten-fold lower rate of iodothyronine metabolism when compared to rat hepatocytes (de Jong et al 1993, van Stralen et al 1993.…”