Deiodinase brain

In contrast to the type I deiodinase which shows a high preference for rT4 over T4 as the substrate (Table II), the type II enzyme is somewhat more effective in the deiodination of T4 than of rT3 (Table III). Under the conditions tested, the Km value of T4 for the type II enzyme is three orders of magnitude lower than the Km of T4 for the type I deiodinase. The Km of rT3 for the type II deiodinase is somewhat greater than that of T4 and differs less from the Km of rT3 for the type I enzyme. The Umax of the conversion of T4 to T3 by the type II enzyme depends on the tissue and the thyroid status of the animal (see below). In cerebral cortex of hypothyroid rats [82] it is roughly one-thousandth of the maximum T3 production by the hepatic type I deiodinase of euthyroid animals determined under similar conditions [32]. The VmiJKm ratio of this reaction is, therefore, similar for the type II deiodinase of hypothyroid rat brain and the type I deiodinase of euthyroid rat liver and much greater than that for the hepatic enzyme of hypothyroid rats [86], In view of the reaction kinetics of the type II deiodinase (see below), it is questionable if the Vm,JKm ratios estimated in vitro also apply to physiological conditions with unknown cofactor availability. 

Evidence has accumulated for the existence of a specific deiodinase for the inner ring of iodothyronines which is further distinguished from the type I enzyme because of its insensitivity to sub-mM PTU concentrations. Thus, type III iodothyronine deiodinase converts T4 to rT3 but not to T3 and produces 3,3 -T2 from T3 but not from rT, (Table I). It has been detected in chick embryo heart [94] and liver [95] cells, monkey hepatocarcinoma cells [96], rat CNS [71,75,97], human [98], rat [98] and guinea pig [99] placenta, and rat skin [100], With higher enzyme activities in cerebral cortex than in cerebellum, the distribution of the type III deiodinase is different from that of the type II enzyme [75], In brain cell cultures type III deiodination appears associated with the presence of glial cells [76,78,79],... 

Figure 5 is a model of the peripheral metabolism of thyroid hormone in normal humans which places the production of plasma T3 and the clearance of plasma rT3 predominantly in tissues with PTU-sensitive, type I deiodinase activity. Although the role of the liver is emphasized, contribution of the kidneys is not excluded. Clearance of plasma T3 and production of plasma rT3 is located mainly in tissues such as brain and perhaps skin with PTU-insensitive, type III deiodinase activity. 

Type II deiodinase occurs in the brain and brown adipose tissue of rats (but not in muscle of rats), and in the brain, skeletal muscle, heart, and thyroid gland in humans (Fallud et al 1997). This enzyme catalyzes the conversion of T4 to T3. When the thyroid gland is stimulated, the type II deiodinase takes on an increased importance in the conversion of T4 to T3 (Salvatore et at., 1996). Type II deiodinase is unique among the deiodinases in that it appears to contain two selenium atoms, rather than just one. The physiological role of the enzyme is to utilize T4 acquired from the bloodstream and to convert it to T3 within the target tissue. 

Type III deiodinase catalyzes the conversion of T4 to reverse T3, and the conversion of T3 to T2- These steps constitute 5 -deiodination reactions. The enzyme occurs in the brain and skin of rats. The physiological role of the type III enzyme is thought to be to protect the brain from possible toxic effects of active thyroid hormone (T3). The placenta is distinguished in that it contains both type II and type III deiodinases (Glinoer, 1997). 

The various deiodinases respond in different ways to selenium deficiency. Studies with rats revealed that nutritional Sc deficiency results in a decline in activity of the type I enzyme in the liver and kidney with little effect on the type 1 activity in the thyroid gland, and with little effect on the type II and type III enzymes in the brain (Pallud, 1997). 

Type II deiodinase activity was significantly increased in fetal, but not maternal brain in the treatment group. T4-UDP-GT activity in maternal liver was significantly increased in the treatment group. These... 

Selenium is a component of all three members of the deiodinase enzyme family, the enzymes responsible for deiodination of the thyroid hormones (Kohrle 1994 St. Germain and Galton 1997). The deiodinases contain a selenocysteine at the active site, which is required for catalytic activity. There are three types of deiodinases and they differ in terms of tissue distribution, reaction kinetics, efficiency of substrate utilization, and sensitivity to inhibitors. The first to be recognized as a selenoprotein was type I iodothyronine 5 -deiodinase which converts the prohormone thyroxine (T4) to the active form, triiodothyronine (T3) and to date, studies of the effects of excess selenium have focused on this protein. Under normal circumstances the human thyroid produces only 20-30% of its hormone as T3 the remainder is T4 (a minute amount of reverse T3 (rT3) is also produced), which is largely converted to active T3 by type I deiodinase located within the liver, euthyroid pituitary, kidney, thyroid, and brain. Type I deiodinase is a membrane bound protein and, thus, its activity has not been directly measured in studies of humans supplemented with selenium. Human studies have instead measured serum levels of T3, rT3, T4, and TSH. 

Adaptive changes in deiodinase activity have been reported in certain regions of the brain of fetal rats exposed in utero to the PCB mixture Aroclor in order to compensate the local depression ofT4 levels (Morse et al, 1996). In chicken embryos, in ovo exposure to PCB77 temporarily reduced TH levels (Roelens et al., 2005) both in plasma and brain areas, which was combined with an adaptive increase in the activity of the type 2 deiodinase activity and decrease in activity of the T3 inactivating type 3 deiodinase Beck V. (2006). 

In a recent study, the ontogenic patterns of T4, T3, rT3 and the deiodinases D2 and D3 activity have been studied in several cerebral areas from fetuses of 13 to 20 weeks (postmenstrual age) and in premature infants that died at 24—42 weeks (postmenstrual age) (Kester et ai, 2004). There are clear temporal and spatial patterns of development for the deiodinases and the concentrations of iodothyronines (Figure 64.5). T3 increases in the cerebral cortex to levels comparable to those reported in adults by the middle of gestation (Calvo et ai, 1998). D2 activity increases in parallel in this region, while D3 activity is very low. On the contrary, cerebellum exhibited high D3 activities that decreased toward midgestation, while T3 was very low in the fetal cerebellum. Other cerebral areas were also examined. This study confirms the importance of both D2 and D3 deiodinases for the bioavailability of T3 in specific brain regions of the human fetus at precise periods of brain development. 

Maternal transfer ofT4 during gestation has a protective role during the development of the fetal brain, as most of the T3 in the fetal brain is locally produced from T4 by D2 deiodinase. 

The concentrations of T3 are controlled by deiodinases type 1 (Dl), 2 (D2), and 3 (D3). D2 transformsT4 intoT3, whereas D3 transforms T4 and T3 into inactive products, reverse T3 and 3, 3 -diiodothyronine, respectively (Bernal et al, 2003). Development regulates the expression and local activity of D2 and D3 in the brain (Kaplan and Yaskoski, 1981). In addition, despite the restricted access of molecules fi-om the blood to the brain parenchyma due to the blood-brain barrier, small amounts of T4 and T3 may enter the brain in the fetus through specific transporters (Sugiyama etaL, 2003). T3 is formed by deiodination ofT4 and defivered... 

Three types of deiodinases are currently known, and these are distinguished from each other primarily based on their location, substrate preference, and susceptibility to inhibitors. Type I deiodinase is found in liver and kidney and catalyzes both inner ring and outer ring deiodination (i.e., T4 to T3 and rTs to 3,3 -T2). Type II deiodinase catalyzes mainly outer ring deiodination (i.e., T4 to T3 and T3 to 3,3 -T2) and is found in brain and the pituitary. Type III deiodinase is the principal source of rTs and is present in brain, skin, and placenta (14). 

Thus the Type I 5 deiodinase activity in cerebral cortex, like that in the liver, requires an active sulfhydryl group, the carboxymethylation of which causes enzyme inactivation. In hypothyroid animals, most of the rT3 is deiodinated by the Type II pathway, since the Type I activity is reduced, and Type II activity increased several fold. Further studies with brain and brown adipose tissue microsomes have shown that the sensitivity of Type II activity to PTU is inversely related to the DTT concentration used during the assay, so that it is important to keep this factor in mind when assessing the sensitivity of a particular enzymatic activity to inhibition by this agent (15,16). Interested readers are referred to these references for a more thorough discussion of this complex area. While the two 5 deiodinase activities are quite distinct enzymatically, until such time as the protein sequences are determined, a definitive answer as to their structural similarities cannot be given. 

One cannot assume, however, that thyroid hormone economy in brain can be entirely understood by the study of the deiodinases, even though some general principles can be derived from such experiments. The... 

---