ONTOGENY OF IODOTHYRONINE DEIODINASES IN HUMAN LIVER

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 a ctivities 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 infan ts (27-32 weeks gestation), and 13 term infants who survived up to 39 weeks postnatally. D1 activity was determined using 1 mu M [3',5'-I-12 5]rT(3) as substrate and 10 mM dithiothreitol (DTT) as cofactor, D2 ac tivity using 1 nM [3',5'-I-125]T-4 and 25 mM DTT in the presence of 1 mM 6-propyl-2-thiouracil (to block D1 activity) and 1 mu M T-3 (to blo ck D3 activity), and D3 activity using 10 nM [3,5-I-125]T-3 and 50 mM DTT, by quantitation of the release of I-125(-). The assays were valid ated by high performance liquid chromatography of the products, and ki netic analysis [Michaelis-Menten constant (K-m) of rT(3) for D1: 0.5 m u M; K-m of T-3 for D3: 2 nM]. In liver homogenates, D1 activity was n ot correlated with age, whereas D3 activity showed a strong negative c orrelation with age (r -0.84), with high D3 activities in preterm infa nts and (except in 1 infant of 35 weeks) absent D3 activity in full-te rm infants. In microsomes, D1 activities amounted to 4.3-60 pmol/min/m g 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 pr otein in fetuses and <0.1 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 findi ngs indicate high D1 and D3 activities in fetal human liver, and high D1 and mostly absent D3 activities in adult human liver. Therefore, th e 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 i ntriguing and deserves further investigation.