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Original Studies |
Department of Internal Medicine III, Erasmus University Medical School (M.H.A.K., E.K., T.J.R., C.H.v.D., T.J.V.), and the Department of Pediatric Surgery, Erasmus University Medical School and Sophia Children Hospital (M.H.A.K., D.T.), 3000 DR Rotterdam, The Netherlands; the Department of Toxicology, German Institute of Human Nutrition (W.M., H.G.) D-14558, Potsdam-Rehbrucke, Germany; and the Department of Molecular and Cellular Pathology, University of Dundee (M.W.H.C.), Dundee DD1 9S4, Scotland
Address all correspondence and requests for reprints to: Dr. Theo J. Visser, Department of Internal Medicine III, Erasmus University Medical School, Room Bd 234, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: visser{at}inw3.azr.nl
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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An intriguing characteristic of D1 is that its deiodination of a number of iodothyronines is accelerated by sulfation of their phenolic hydroxyl group (4, 5). Thus, IRD of both T4 sulfate (T4S) and T3 sulfate (T3S) by rat D1 is 40–200 times faster than deiodination of the nonsulfated substrates. In contrast, ORD of T4 by rat D1 is completely blocked by sulfation (4, 5). This is not a general phenomenon, as ORD of rT3 by rat D1 is not affected by sulfation, whereas ORD of 3,3'-T2 by rat D1 is accelerated about 50-fold by sulfation of this compound (4, 5). Similar findings have been obtained with human and dog D1 (8, 9). The facilitated deiodination of sulfated iodothyronines is a unique property of D1. Neither the type II iodothyonine deiodinase (D2), which catalyzes only ORD, e.g. T4 to T3 and rT3 to 3,3'-T2, nor the type III iodothyronine deiodinase (D3), which catalyzes only IRD, e.g. T4 to rT3 and T3 to 3,3'-T2, is capable of catalyzing the deiodination of sulfated iodothyronines (10, 11).2
Serum concentrations of T4S, T3S, rT3S, and 3,3'-T2S are low in normal human subjects, but they are high in fetal and cord blood, in patients with nonthyroidal illness, and in patients treated with propylthiouracil or iopanoic acid, inhibitors of D1 (12, 13, 14, 15, 16, 17, 18, 19). The serum T3S/T3 ratio is also increased in hypothyroid patients (13). High serum T4S, T3S, rT3S, and 3,3'-T2S levels have also been detected in serum, bile, allantoic fluid, and amniotic fluid of fetal sheep (19, 20, 21, 22). The high serum iodothyronine sulfate levels during nonthyroidal illness, hypothyroidism, and fetal development have been ascribed to a low peripheral D1 activity in these conditions (4, 5, 11). These results are in accordance with experimental findings in rats showing marked increases in the serum concentration and biliary excretion of iodothyronine sulfates in animals with impaired hepatic and renal D1 activities due to administration of D1 inhibitors or selenium deficiency (23, 24, 25, 26, 27). These changes are not caused by an increased sulfation of iodothyronines, but, rather, by a decreased clearance of the sulfated iodothyronines by D1 (24, 28). Thus, sulfation is a primary step leading to the irreversible degradation of T4 and T3 by D1. However, if D1 activity is low, inactivation of thyroid hormone by sulfation is reversible due to expression of sulfatases in different tissues and by intestinal bacteria (11, 29, 30, 31). It has been speculated that especially in the fetus, T3S has an important function as a reservoir from which active T3 may be released in a tissue-specific and time-dependent manner (5, 11).
Sulfation of the hydroxyl group of a variety of substrates is catalyzed by a family of homologous sulfotransferases located in the cytoplasmic fraction of different tissues, such as liver, kidney, intestine, and brain (1, 2, 3). All of these isoenzymes use 3'-phosphoadenosine-5'-phosphosulfate (PAPS) as sulfate donor (1, 2, 3). On the basis of substrate specificity and amino acid sequence homology, two sulfotransferase families have been recognized in human tissues, i.e. phenol sulfotransferases (including estrogen sulfotransferases) and hydroxysteroid sulfotransferases (1, 2, 3). It is not known which sulfotransferases are involved in the sulfation of iodothyronines in human tissues. Previous studies have suggested a role for the enzymes termed phenol-preferring phenol sulfotransferase (P-PST) and monoamine-preferring phenol sulfotransferase (M-PST), in the sulfation of T3 in human liver and intestine (32, 33). Recently, a large number of human and rat sulfotransferases have been cloned and characterized, including human SULT1A1 and SULT1A3, which represent P-PST and M-PST, respectively (34, 35, 36), under a new nomenclature system. Here we report the results of a comparison of the kinetic profiles of the sulfation of iodothyronines by human liver and kidney cytosol and by recombinant preparations of human SULT1A1 and SULT1A3.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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[3',5'-125I]T4 and [3'-125I]T3 were obtained from Amersham (Aylesbury, UK); T4, T3, and PAPS from Sigma Chemical Co. (St. Louis, MO); rT3, 3,5-T2, 3,3'-T2, 3',5'-T2, 3- and 3'-iodothyronine (T1), and thyronine (T0) from Henning (Berlin, Germany); and Sephadex LH-20 from Pharmacia (Woerden, The Netherlands). 3,[3'-125I]T2 and [3',5'-125I]rT3 were prepared by radioiodination of 3-T1 and 3,3'-T2, respectively, as previously described (37).
Normal adult human liver and kidney tissues were obtained at surgery for liver and kidney tumors. Approval was obtained from the medical ethical committee of Erasmus University Medical School and Hospital. Tissue was homogenized in 0.25 mol/L sucrose, 10 mmol/L HEPES (pH 7.0), and 1 mmol/L dithiothreitol, and cytosol was prepared as previously described (8). SULT1A1 complementary DNA (cDNA) cloned by Wilborn et al. (34) and SULT1A3 cDNA cloned by Ganguly et al. (36) were provided by Dr. C. N. Falany (University of Alabama, Birmingham, AL) and expressed in Salmonella typhimurium as previously described (38). Human SULT1A3 cDNA was also cloned from human platelets and expressed in V79 cells (35). Bacterial and V79 cell cytosols were prepared for characterization of recombinant sulfotransferase activities (35, 38). Protein was measured with the Bio-Rad protein assay (Bio-Rad, Veenendaal, The Netherlands), using BSA as the standard.
Sulfotransferase assay
Iodothyronine sulfotransferase activities were analyzed by incubation of 0.1 µmol/L T4, T3, rT3, or 3,3'-T2 and 100,000 cpm of the 125I-labeled compound for 30 min at 37 C with the indicated amounts of liver or kidney cytosol or recombinant sulfotransferase preparation in the presence or absence (blank) of 50 µmol/L PAPS in 0.2 mL 0.1 mol/L phosphate (pH 7.2) and 2 mmol/L ethylenediamine tetraacetate (39). Similar results were obtained in the absence of ethylenediamine tetraacetate. The reactions were started by the addition of enzyme diluted in ice-cold buffer and were stopped by the addition of 0.8 mL 0.1 mol/L HCl. The mixtures were analyzed for sulfoconjugate formation by chromatography on Sephadex LH-20 minicolumns as previously described (39). Sulfation in reaction mixtures with PAPS was corrected for background radioactivity detected in the corresponding Sephadex LH-20 fractions of the blanks. Incubations were carried out in triplicate, and the coefficient of variation was less than 10%.
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Results |
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shows the sulfation of 0.1
µmol/L T4, T3,
rT3, and 3,3'-T2 by human
liver and kidney cytosol, SULT1A1, and SULT1A3 in the presence of 50
µmol/L PAPS. All enzyme preparations display a strong substrate
preference for 3,3'-T2, which is sulfated
approximately 2 orders of magnitude more rapidly than
T3 and rT3, whereas
T4 is a poor substrate for these human
sulfotransferases.
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presents the sulfation of 3,3'-T2 by
human liver cytosol in the presence of PAPS as a function of incubation
time and cytosolic protein concentration. Under the conditions used,
3,3'-T2 sulfation was linear with incubation time
up to 45 min, when about 50% of the substrate was converted (Fig. 2A). The subsequent decrease in sulfation
rate was probably due to depletion of substrate rather than depletion
of cofactor, because PAPS was added in large excess (50 µmol/L).
Initially, 3,3'-T2 sulfation showed a more than
proportional increase with the cytosolic protein concentration (Fig. 2B). For instance, an increase in the cytosolic protein concentration
from 25 to 50 µg/mL resulted in a 3-fold increase in
3,3'-T2S formation. Further increases in protein
concentration resulted in roughly linear increases in
3,3'-T2 sulfation until significant substrate
depletion occurred. Similar results were obtained when
3,3'-T2 sulfation by human kidney cytosol was
analyzed as a function of the cytosolic protein concentration (data not
shown).
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shows the sulfation of
3,3'-T2 by human liver (A) and kidney (B) cytosol
as a function of the substrate concentration. In both tissues,
saturation kinetics were observed in the range of the
3,3'-T2 concentrations tested, with maximum
sulfation rates obtained at 3 µmol/L 3,3'-T2.
At higher 3,3'-T2 concentrations, a decrease in
the sulfation rate was observed, suggesting substrate inhibition. The
double reciprocal plots of sulfation rate vs.
3,3'-T2 concentration were linear, allowing the
calculation of apparent Km values for
3,3'-T2 and maximal velocity
(Vmax) values. Table 1 presents the kinetic parameters for
3,3'-T2 sulfation by human liver and kidney
cytosol at 50 µmol/L PAPS determined in different experiments. The
mean apparent Km for
3,3'-T2 was 1.02 µmol/L in liver and 0.64
µmol/L in kidney cytosol. The data presented were obtained using
three different kidney samples and two different cytosol preparations
from the same liver, whereas very similar results were obtained with 59
other liver samples.3 Table 1
also gives the kinetic parameters for the sulfation of
T3 determined under similar conditions. Compared
with 3,3'-T2, apparent Km
values for T3 were approximately 50-fold higher,
i.e. 54.9 µmol/L in liver and 27.8 µmol/L kidney,
whereas apparent Vmax values were roughly 10-fold
lower.
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depicts the sulfation of
3,3'-T2 by SULT1A1 (A) and SULT1A3 (B) as a
function of the substrate concentration. Maximum sulfation rates were
obtained at lower 3,3'-T2 concentrations for
SULT1A1 than for SULT1A3, with SULT1A1 showing clear substrate
inhibition at 3,3'-T2 levels above 1 µmol/L.
From the linear double reciprocal plots, apparent
Km and Vmax values were
calculated. As the enzymes expressed in Salmonella and V79
cells were tested as crude cytosol, the maximum sulfation rates
determined in these experiments are not representative of the
differences in kcat values between the different
isoenzymes. The kinetic parameters determined in different experiments
are summarized in Table 1
, showing mean Km values
of 0.14 and 33 µmol/L for 3,3'-T2 sulfation by
SULT1A1 and SULT1A3, respectively. Apparent Km
values were identical for SULT1A3 expressed in either
Salmonella or V79 cells. Again, T3
sulfation was characterized by much higher apparent
Km values, i.e. 29.1 µmol/L for
SULT1A1 and 112 µmol/L for SULT1A3, and lower apparent
Vmax values compared with those for
3,3'-T2 (Table 1).
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shows the effects of increasing
PAPS concentration on the sulfation of 0.1 µmol/L
3,3'-T2 by human liver (A) and kidney (B)
cytosol. Sulfation approached maximum rates at PAPS concentrations of
30 µmol/L or more. The double reciprocal plots of these data were
linear, from which Km and
Vmax values (at 0.1 µmol/L
3,3'-T2) were calculated. Table 1 summarizes the
results from different experiments. The mean apparent
Km value for PAPS was 6 µmol/L in liver and 9
µmol/L in kidney cytosol.
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presents the sulfation of 0.1
µmol/L 3,3'-T2 by SULT1A1 (A) and SULT1A3 (B)
as a function of the PAPS concentration. The PAPS concentration
required for maximum sulfation rates was lower for SULT1A1 than for
SULT1A3. The apparent Km values for PAPS (at 0.1
µmol/L 3,3'-T2) calculated from the linear
Lineweaver-Burk plots were 0.65 and 2.7 µmol/L, respectively .
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demonstrates the effects of
increasing concentrations (1–100 µmol/L) of unlabeled iodothyronines
on the sulfation of 3,[3'-125I]T2
(1 µmol/L) by human liver cytosol. T0 had no effect,
whereas 3-T1 and 3,5-T2 produced only
10–20% inhibition at the highest concentration tested. All other
iodothyronines inhibited the sulfation of labeled
3,3'-T2 dose dependently, with potencies
decreasing in the order 3,3'-T2 >
rT3 > 3',5'-T2 >
3'-T1 > T3 
T4.
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compares the effects of unlabeled
iodothyronines (10 µmol/L) on the sulfation of
3,[3'-125I]T2 (1 µmol/L) by human
liver and kidney cytosol, SULT1A1, and SULT1A3. In general, the
magnitude of inhibition of the sulfotransferase activities by the
various iodothyronine analogs decreased in the order SULT1A1 >
liver kidney > SULT1A3. The inhibition profiles of the
tissue sulfotransferase activities were better correlated with the
inhibition profile of SULT1A1 than with that of SULT1A3 (liver
vs. SULT1A1: r = 0.936; P < 0.01;
liver vs. SULT1A3: r = 0.793; P <
0.01; kidney vs. SULT1A1: r = 0.920; P
< 0.01; kidney vs. SULT1A3: r = 0.751;
P < 0.01).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Sulfation of T3 by P-PST and M-PST purified from human liver and intestine has been reported previously (32, 33), but it remains to be determined which SULT1A isoenzyme is most important for thyroid hormone sulfation in human liver and other tissues. In addition to the members of the SULT1A family, two other human phenol sulfotransferases, SULT1B1 (49, 50) and SULT1C1 (47, 48), have been cloned recently. Whereas it is unknown whether isoenzymes homologous to SULT1A2 and SULT1A3 exist in rats, the rat homologs of human SULT1A1, SULT1B1, and SULT1C1 have been cloned and characterized regarding their activity toward iodothyronines (51, 52, 53). These studies have demonstrated that both rat SULT1B1 and SULT1C1 catalyze the sulfation of different iodothyronines, in particular 3,3'-T2, whereas rat SULT1A1 is completely inactive. Human SULT1B1 has recently also been shown to have sulfotransferase activity toward iodothyronines (50), but sulfation of iodothyronines by human SULT1C1 has not yet been reported.
We demonstrate that both human SULT1A1 and SULT1A3 are capable of catalyzing the sulfation of iodothyronines. This is not surprising, as the sulfation of T3 by P-PST and M-PST purified from human liver and intestine has been reported previously (32, 33). We have also recently demonstrated effective sulfation of iodothyronines by human SULT1A2.4 It appears that small differences in amino acid sequence can effect large differences in sulfotransferase activity. The high activity of human SULT1A1 in contrast to the complete lack of iodothyronine sulfotransferase activity of rat SULT1A1 is remarkable, considering the high degree of amino acid sequence identity (80%) between these orthologous proteins (2, 51). Likewise, the smaller (8%) difference in amino acid sequence between human SULT1A1 and SULT1A3 (34, 35, 36, 46) is associated with a more than 200-fold difference in the Km value for 3,3'-T2, a 4-fold difference in the Km value for T3, and a 4-fold difference in the Km value for PAPS. It should be noted that the apparent Km value of 3,3'-T2 for SULT1A1 presented here is about 10-fold lower than that mentioned previously (53), which may be due to partial inactivation through oxidation (54) of the enzyme preparation used previously.
The main purpose for comparing the substrate specificities and kinetic parameters of native iodothyronine sulfotransferase activities in human liver and kidney with these properties of recombinant sulfotransferases is to try to identify the isoenzymes that contribute most to the sulfation of thyroid hormone in these tissues. The iodothyronine sulfotransferase activities of human liver and kidney cytosol are characterized by similar apparent Km values for both 3,3'-T2 and PAPS as well as similar substrate specificities, suggesting the involvement of similar isoenzymes. The substrate specificities of the hepatic and renal sulfotransferase activities showed a better correlation with SULT1A1 than with SULT1A3, suggesting that SULT1A1 is a prominent iodothyronine sulfotransferase in human liver and kidney. However, the different iodothyronines showed a lower apparent affinity for the native sulfotransferases than for recombinant SULT1A1, which may be due to the presence of iodothyronine-binding proteins in the tissues. Sulfation of thyroid hormone in human liver and kidney (and possibly other tissues) involves contributions of at least SULT1A1, SULT1A2, SULT1A3, and SULT1B1 and perhaps also SULT1C1. The complexity is further increased by the polymorphic variation in these isoenzymes (2, 55) and their tissue-specific expression (56). In addition, it has been demonstrated that functional rat phenol sulfotransferases may consist of either two identical (homodimer) or two different subunits (heterodimer) (57). Our findings of a more than linear increase in iodothyronine sulfotransferase activity with an increase in hepatic or renal cytosolic protein concentration may reflect this requirement for protein dimerization.
The native and recombinant sulfotransferases tested in this study show a marked preference for 3,3'-T2 as the substrate. Both SULT1A1 and SULT1A3 are much less efficient in catalyzing the sulfation of T3, which does not imply that these isoenzymes are not important for T3 sulfation in vivo. This is supported by the significant sulfation of T3 in both human liver and kidney cytosol. Sulfation of T4 is almost undetectable, not only with recombinant SULT1A1 and SULT1A3 but also in human liver and kidney. Nevertheless, high serum T4S levels have been detected in human newborns (14, 15), suggesting sulfation of T4 by other isoenzymes.
In conclusion, we have identified SULT1A1 and SULT1A3 as low Km and high Km human iodothyronine sulfotransferases, respectively, and obtained evidence that the sulfation of iodothyronines in human liver and kidney is catalyzed by similar enzymes. Further investigations are required to determine the possible importance of other isoenzymes, such as SULT1A2, SULT1B1, and SULT1C1, and of polymorphic variations in the different sulfotransferases for the sulfation of thyroid hormone in human tissues. This information is essential for investigation of the regulation of this important pathway of thyroid hormone metabolism under (patho)physiological conditions, in particular during fetal development.
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Acknowledgments |
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Footnotes |
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2 Visser, T. J., and E. Kaptein, unpublished
work.
3 Gilissen, R. A. H. J., M.
W. H. Coughtrie, E. Kaptein, and T. J. Visser, unpublished
work.
4 Kester, M. H. A., M. W. H.
Coughtrie, H. Glatt, and T. J. Visser, unpublished work.
Received July 17, 1998.
Revised November 9, 1998.
Accepted January 7, 1998.
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