Characterization of rat iodothyronine sulfotransferases
Monique H. A. Kester,1
Ellen Kaptein,1
Thirza J. Roest,1
Caren H. van Dijk,1
Dick Tibboel,2
Walter Meinl,3
Hansruedi Glatt,3
Michael W. H. Coughtrie,4 and
Theo J. Visser1
Departments of 1Internal Medicine and
2Pediatric Surgery, Erasmus Medical Center, 3015 GE
Rotterdam, The Netherlands; 3Department of Toxicology,
German Institute of Human Nutrition, D-14558 Potsdam-Rehbrücke, Germany;
and 4Department of Molecular and Cellular Pathology,
University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom
Submitted 31 January 2003
; accepted in final form 19 May 2003
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ABSTRACT
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Sulfation appears to be an important pathway for the reversible
inactivation of thyroid hormone during fetal development. The rat is an often
used animal model to study the regulation of fetal thyroid hormone status. The
present study was done to determine which sulfotransferases (SULTs) are
important for iodothyronine sulfation in the rat, using radioactive
T4, T3, rT3, and 3,3'-T2 as
substrates, 3'-phosphoadenosine-5'-phosphosulfate (PAPS) as
cofactor, and rat liver, kidney and brain cytosol, and recombinant rat
SULT1A1, -1B1, -1C1, -1E1, -2A1, -2A2, and -2A3 as enzymes. Recombinant rat
SULT1A1, -1E1, -2A1, -2A2, and -2A3 failed to catalyze iodothyronine
sulfation. For all tissue SULTs and for rSULT1B1 and rSULT1C1,
3,3'-T2 was by far the preferred substrate. Apparent
Km values for 3,3'-T2 amounted to 1.9
µM in male liver, 4.4 µM in female liver, 0.76 µM in male kidney,
0.23 µM in male brain, 7.7 µM for SULT1B1, and 0.62 µM for SULT1C1,
whereas apparent Km values for PAPS showed less variation
(2.0-6.9 µM). Sulfation of 3,3'-T2 was inhibited dose
dependently by other iodothyronines, with similar structure-activity
relationships for most enzymes except for the SULT activity in rat brain. The
apparent Km values of 3,3'-T2 in liver
cytosol were between those determined for SULT1B1 and -1C1, supporting the
importance of these enzymes for the sulfation of iodothyronines in rat liver,
with a greater contribution of SULT1C1 in male than in female rat liver. The
results further suggest that rSULT1C1 also contributes to iodothyronine
sulfation in rat kidney, whereas other, yet-unidentified forms appear more
important for the sulfation of thyroid hormone in rat brain.
thyroid hormone; sulfation; rat sulfotransferase 1B1; rat sulfotransferase 1C1
SULFATION IS A METABOLIC REACTION that facilitates the excretion
of endogenous and exogenous hydrophobic compounds in bile and urine by
increasing their water solubility
(5,
9,
16,
35). Biliary excretion of
iodothyronines is also increased by sulfation. More importantly, however,
sulfation appears to be a key step in the inactivation of thyroid hormone. The
prohormone thyroxine (T4) is converted by outer-ring deiodination
(ORD) to the biologically active 3,3',5-triiodothyronine (T3)
or by inner-ring deiodination (IRD) to the inactive
3,3',5'-triiodothyronine (rT3)
(42). By sulfation,
T3 loses its affinity for the thyroid hormone receptors
(41). Additionally,
T3 sulfate (T3S) is subject to accelerated degradation,
as sulfation facilitates the IRD of T3 by the type I deiodinase
(D1) (42). Sulfation also
facilitates the inactivating IRD of T4 by D1, whereas the
activating ORD of T4 by D1 is completely blocked by sulfation
(42). Therefore, an important
function of sulfation is to facilitate the irreversible degradation of thyroid
hormone. Furthermore, under conditions in which the deiodinative clearance of
sulfates is impaired, sulfation may be reversed by sulfatases. Because
T3S and T4S levels in the human fetal circulation are
high (4,
38,
40), it has been speculated
that sulfation is a mechanism to protect the fetus from excessive
T3 and that sulfation/desulfation plays an important role in the
regulation of thyroid hormone bioactivity during fetal development
(27,
34,
39). The exact mechanism for
the increased iodothyronine sulfate levels in the fetal circulation is
unclear, but the reversible nature of this inactivation step contrasts with
the irreversible nature of type III deiodinase (D3)-catalyzed IRD, which is
also extensive during fetal development
(3,
14,
15,
26,
33).
Sulfation is catalyzed by cytosolic sulfotransferases present in a wide
range of tissues. The sulfotransferases transfer the sulfuryl group of
3'-phosphoadenosine-5'-phosphosulfate (PAPS) to usually OH groups
of their substrates (5,
16). All cytosolic
sulfotransferases are members of a single gene superfamily, termed SULT. A
systematic nomenclature is in preparation but not yet finalized. It is already
widely used for human (h)SULTs but not for rat (r)SULTs.
Table 1 indicates the
designations of the rSULTs used in the present study together with synonymous
names that have been used elsewhere. On the basis of amino acid sequence
homology, three families of sulfotransferases have been identified in humans:
the SULT1 family, which primarily represents phenol sulfotransferases,
including hSULT1A1, -1A2, -1A3, -1B1, -1C2, -1C4, and -1E1, the SULT2 family,
which usually prefers alcoholic substrates, including hydroxysteroids, and the
SULT4 family, containing sulfotransferase-like proteins for which no
substrates have been identified yet
(5,
9,
16,
35). In the rat, the phenol
sulfotransferases rSULT1A1, -1B1, -1C1, -1C2, -1C3, -1D1, -1E1, and -1E2, the
hydroxysteroid sulfotransferases rSULT2A1, -2A2, and -2A3, and the
sulfotransferase-like protein rSULT4A1 have been cloned
(5,
9,
16,
18,
35,
45). For several human and rat
phenol sulfotransferases, allelic variants have been identified
(5,
9,
16,
18,
45). Another important
observation is that the sulfotransferases may not exist only as homodimers but
also as heterodimers (25).
Sulfation of iodothyronines is catalyzed by phenol sulfotransferases.
Recently, we identified hSULT1A1, -1A3, -1B1, and 1E1 as human iodothyronine
sulfotransferases (23,
24). Because the rat is the
most frequently studied animal model for in vivo iodothyronine metabolism, we
set out to characterize the sulfation of different iodothyronines by rat
liver, kidney, and brain cytosol and by recombinant preparations of rSULT1A1,
-1B1, -1C1, -1E1, -2A1, -2A2, and -2A3 to identify which sulfotransferases are
important for iodothyronine sulfation in the rat.
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MATERIALS AND METHODS
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Materials. Male and female Wistar rat liver cytosols and male
Wistar rat kidney and brain cytosols were obtained as previously described
(43). Approval was obtained
from the Erasmus Committee of Animal Welfare. rSULT1C1 cDNA
(32) was kindly provided by
Dr. Y. Yamazoe and expressed in V79 cells as previously described
(17). rSULT1A1 cDNA
(20) was kindly provided by
Dr. C. N. Falany and expressed in Salmonella typhimurium
(18). rSULT2A1, -2A2, and -2A3
were cloned and expressed in S. typhimurium, and rSULT2A1 was also
expressed in V79 cells (6,
17). rSULT1B1, an rSULT1C1
variant containing amino acid substitutions S2A, T60A, and S96P, and rSULT1E1
and -2A3 were cloned by RT-PCR and expressed in S. typhimurium
(18). V79 and bacterial cell
cytosols were prepared as previously described
(17).
[3',5'-125I]T4 and
[3'-125I]T3 were obtained from Amersham
Biosciences (Amersham, UK); T4, rT3, T3,
3,5-, 3,3'-, and 3',5'-diiodothyronine (T2), 3-
and 3'-iodothyronine (T1), and thyronine (T0) were
purchased from Henning Berlin (Berlin, Germany); PAPS was obtained from Sigma
(St. Louis, MO); and Sephadex LH-20 were obtained 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
(31).
Sulfotransferase assays. Iodothyronine sulfotransferase activities
were analyzed by incubation of usually 0.1 or 1 µM T4,
T3, rT3, or 3,3'-T2 and 105
cpm of the 125I-labeled compound for 30 min at 37°C with the
indicated amounts of liver, kidney, or brain cytosol or recombinant
sulfotransferase in the presence or absence (blank) of 50 µM PAPS in 0.2 ml
of 0.1 M phosphate (pH 7.2) and 2 mM EDTA. The reactions were stopped by
addition of 0.8 ml of 0.1 M HCl. The mixtures were analyzed for iodothyronine
sulfate formation by chromatography on Sephadex LH-20 minicolumns as
previously described (22).
Enzymatic sulfation was corrected for background radioactivity detected in the
blanks.
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RESULTS
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Figure 1 shows the sulfation
of 0.1 µM T4, T3, rT3, and
3,3'-T2 by male and female rat liver cytosol, male rat
kidney, and brain cytosol, and rSULT1B1 and -1C1 in the presence of 50 µM
PAPS. All enzyme preparations show a substrate preference for
3,3'-T2. Rates of 3,3'-T2 sulfation are
>50-fold higher than those of T3 and rT3 sulfation;
T4 is the poorest substrate for all enzyme preparations. rSULT1A1,
-1E1, -2A1, -2A2, and -2A3 did not catalyze iodothyronine sulfation (data not
shown).

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Fig. 1. Sulfation of iodothyronines by male (M) and female (F) rat liver cytosol,
male rat kidney, and brain cytosol, rat sulfotransferase (rSULT)1B1 and
rSULT1C1. Reaction conditions were 0.1 µM 125I-labeled thyroxine
(T4), 3,3',5-triiodothyronine (T3), inactive
3,3',5'-T3 (rT3), or
3,3'-diiodothyronine (T2), 0.1 mg protein/ml, 50 µM
3'-phosphoadenosine-5'-phosphosulfate (PAPS), and 30-min
incubation. Results are means of triplicate determinations from a
representative experiment.
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Figure 2 shows the sulfation
of 3,3'-T2 by female rat liver or male rat liver, kidney, or
brain cytosol as a function of the substrate concentration. Maximum sulfation
rates were obtained at
10 µM 3,3'-T2 in male and
female rat liver cytosol, at
2 µM in male rat kidney cytosol, and at
1 µM in male rat brain cytosol. Rat brain cytosol showed clear
substrate inhibition for 3,3'-T2 at concentrations above 1
µM. Km and Vmax values for the
different tissue cytosols were calculated from the linear double-reciprocal
plots of sulfation rate vs. 3,3'-T2 concentration and are
presented in Table 2.
Vmax values decreased in the order male liver > female
liver > brain > kidney. Km values for T3
sulfation by the tissue cytosols, which were determined under the same
conditions, were >50-fold higher than for the sulfation of
3,3'-T2 (data not shown).

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Fig. 2. Effects of substrate concentration on sulfation of 3,3'-T2
by female or male rat liver cytosol, male rat kidney, or brain cytosol.
Insets: double-reciprocal plot. Reaction conditions were 0.1-25 µM
[3,3'-125I]T2, 25 (male liver), 50 (female liver
and male brain) or 250 (male kidney) µg protein/ml, 50 µM PAPS, and
30-min incubation. Results are means of triplicate determinations from a
representative experiment.
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Figure 3 depicts the
sulfation of 3,3'-T2 by rSULT1B1 or -1C1 as a function of the
substrate concentration. For rSULT1C1, maximum sulfation rates were obtained
at lower 3,3'-T2 concentrations than for rSULT1B1. The
decrease in sulfation rate for rSULT1C1 at concentrations above 1 µM
indicated substrate inhibition. The apparent Km values
calculated from the Lineweaver-Burk plots amounted to 7.7 µM for rSULT1B1
and 0.62 µM for rSULT1C1 (Table
2). Because crude cytosols of rSULT1B1-expressing
Salmonella cells and rSULT1C1-expressing V79 cells were tested, the
Vmax values for the different enzymes are not
representative of their Kcat values. The kinetic
parameters for T3 sulfation by the different isoenzymes are also
presented in Table 2. Compared
with 3,3'-T2, apparent Km values for
T3 were 20- to 150-fold higher. The apparent Km
value determined for 3,3'-T2 sulfation by the rSULT1C1
variant (5.8 µM) was 10-fold higher than for wild-type rSULT1C1.

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Fig. 3. Effects of substrate concentration on sulfation of 3,3'-T2
by rSULT1B1 and rSULT1C1. Insets: double-reciprocal plot. Reaction
conditions were 0.1-30 µM [3,3'-125I]T2, 10
(rSULT1B1) or 25 (rSULT1C1) µg protein/ml, 50 µM PAPS, and 30-min
incubation. Results are means of triplicate determinations from a
representative experiment.
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Because of its higher affinity for the different sulfotransferases,
3,3'-T2 was used in different experiments as a model
substrate for the receptor-active T3.
Figure 4 depicts the sulfation
of 1 µM 3,3'-T2 by male rat liver cytosol at different
PAPS concentrations (1-100 µM). Maximum sulfation rates were reached at
PAPS concentrations
30 µM. Its apparent Km value,
calculated from the Lineweaver-Burk plot, was 4.7 µM. The
Km values for the other enzyme preparations were also in
the low micromolar range, i.e., 3.8 µM for female rat liver, 2.2 µM for
male rat kidney, 3.5 µM for brain cytosol, 2.0 µM for rSULT1B1, and 6.9
µM for rSULT1C1.

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Fig. 4. Effect of PAPS concentration on sulfation of 3,3'-T2 by
male rat liver cytosol. Inset: double-reciprocal plot. Reaction
conditions were 1 µM [3,3'-125I]T2, 1-100 µM
PAPS, 20 µg protein/ml, and 30-min incubation. Results are means of
triplicate determinations from a representative experiment.
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Figure 5 shows the effects
of increasing concentrations (1-100 µM) of unlabeled iodothyronines on the
sulfation of [3,3'-125I]T2 by male rat liver
cytosol. 3,5-T2 had no effect; all other iodothyronines inhibited
the sulfation of labeled 3,3'-T2 dose dependently, in the
order 3,3'-T2
3'-T1 >
3',5'-T2 > rT3 > T4 >
T0
3-T1
T3.

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Fig. 5. Effects of 1-100 µM unlabeled iodothyronines on sulfation of
[3,3'-125I]T2 by male rat liver cytosol. Reaction
conditions were 105 cpm 3,[3'-125I]T2,
25 µg protein/ml, 50 µM PAPS, and 30-min incubation. T1,
3,3',5-iodothyronine; T0, thyronine. Results are means of
triplicate determinations from a representative experiment.
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Figure 6 compares the
effects of 10 µM unlabeled iodothyronines on the sulfation of 1 µM
[3,3'-125I]T2 by male and female liver and male
kidney and brain cytosol, rSULT1B1, and rSULT1C1. 3,3'-T2
sulfation by rSULT1C1 was affected most by the different iodothyronines.
Sulfation of 3,3'-T2 by female rat liver cytosol was
inhibited less potently by the different analogs than 3,3'-T2
sulfation by male rat liver. The structure-activity relationships for
inhibition of T2 sulfation by analogs were similar for female and
male liver, kidney, rSULT1B1, and rSULT1C1. In general, iodothyronines without
iodine substituent in the outer ring (T0, 3-T1,
3,5-T2) and those with two iodines in the inner ring
(3,5-T2,T3,T4) showed little or no
inhibition. In other words, iodothyronines that showed significant inhibition
had zero or one iodine substituent in the inner ring and one or two iodines in
the outer ring.

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Fig. 6. Effects of 10 µM unlabeled iodothyronines on sulfation of 1 µM
[3,3'-125I]T2 by male and female rat liver
cytosol, male rat kidney, and brain cytosol and by rSULT1B1 and rSULT1C1. Data
represent sulfation of [3,3'-125I]T2 in the
presence of unlabeled iodothyronines as a percentage of the control (without
addition of unlabeled iodothyronines). Results are means ± SD of 2-3
experiments.
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The inhibition profiles for rat liver and kidney were significantly
correlated with those for SULT1B1 and -1C1, with coefficients varying between
0.869 and 0.990. However, in contrast to all other enzyme preparations,
3,3'-T2 sulfation by rat brain cytosol was poorly inhibited
by 3'-T1 and 3',5'-T2, and the
inhibition profile for rat brain cytosol also showed weaker correlations with
those for rSULT1B1 (r = 0.814) and rSULT1C1 (r = 0.633).
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DISCUSSION
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In previous studies, hSULT1A1, -1A2, -1A3, -1B1, -1C1, and -1E1 have been
identified as important enzymes for iodothyronine sulfation in humans
(1,
13,
23,
28,
29,
47). rSULT1A1, -1B1, -1C1, and
-1E1 show 79, 74, 63, and 70% amino acid sequence identity, respectively, with
their human homologs, and
50% identity among themselves. Sulfation of
T3 by rat SULT1B1 and -1C1 has been reported previously
(12,
19,
37,
44). In this study, we
compared kinetic parameters and substrate specificities for the different rat
enzymes with these characteristics for female rat liver and male rat liver,
kidney, and brain cytosol in an attempt to determine which enzyme forms are
involved in iodothyronine sulfation in the different tissues. We used
mammalian V79 cells and bacterial S. typhimurium cells as expression
systems for the different SULT enzymes. Previous studies showed that the
different systems give similar results for the various human SULT enzymes
(23).
Iodothyronine sulfotransferase activities in rat liver and kidney and of
rSULT1B1 and -1C1 showed very similar substrate specificities. The higher
maximum sulfation rates observed in male than in female rat liver cytosol are
in agreement with earlier reports on the sex dependence of T3
sulfation in rats, which is explained by the male-dominant expression of
rSULT1C1 (21,
22,
30,
36). rSULT1C1 is predominantly
expressed in male liver, kidney, and intestine, whereas rSULT1B1 expression in
liver, kidney, and intestine is equal in male and female rats
(2,
7,
8). The apparent
Km of 3,3'-T2 in liver cytosol is between
the Km values for SULT1B1 and -1C1, in male liver closer
to that for SULT1C1, and in female liver closer to that for SULT1B1,
supporting a greater contribution of SULT1C1 in male vs. female rat liver. The
apparent Km of 3,3'-T2 in kidney is
similar to the Km for SULT1C1, suggesting that SULT1C1 is
a more important enzyme than SULT1B1 in rat kidney. Although direct comparison
between rSULT1B1 and rSULT1C1 mRNA levels in the different tissues is
difficult, Dunn and Klaassen
(8) showed that rSULT1C1 mRNA
expression is >100-fold higher in liver than in kidney, whereas rSULT1B1
mRNA levels are 10-fold higher in liver than in kidney. In agreement with
this, much higher sulfation rates were found in liver than in kidney
cytosols.
It is, however, possible that, besides SULT1B1 and -1C1, SULT1C2, -1C3, and
-1D1 also contribute to iodothyronine sulfation in the different tissues.
Furthermore, rat phenol sulfotransferases have been demonstrated to exist not
only as homodimers but also as heterodimers
(25). Thus, besides SULT1A1,
-1B1, and -1C1 homodimers, tissues such as liver may contain various
heterodimers. Although SULT1A1 homodimer does not possess sulfotransferase
activity toward iodothyronines, it is not excluded that SULT1A1/1B1 and
-1A1/1C1 heterodimers catalyze iodothyronine sulfation. It is clear that
substrate specificities and apparent Km values determined
in tissue represent average values for mixtures of homo- and heterodimeric
iodothyronine sulfotransferases. Substrate preference and
Km value of 3,3'-T2 in rat brain are
different from those of SULT1B1 and -1C1. Therefore, other enzyme form(s) seem
to be involved in iodothyronine sulfation in rat brain. In agreement with
this, no rSULT1B1 and rSULT1C1 mRNAs were detected in rat brain
(8). A possible candidate is
the recently cloned rat brain sulfotransferase-like protein rSULT4A1
(11). Compared with liver and
kidney, the inhibition profile for rat brain cytosol showed weaker
correlations with those for SULT1B1 and -1C1, also indicating the involvement
of other enzymes. However, assessment of inhibition profiles may be biased if
inhibitors are extensively sulfated themselves by the enzymes under study or
other sulfotransferases, resulting in a decrease in their inhibitory potency.
For instance, the weaker inhibition of 3'-T1 in rat brain may
be explained by its sulfation by different enzymes present in brain.
Concerning the rSULT1C1 variant, mutational analysis should reveal which
amino acid substitution (S2A, T60A, or S96P) contributes most to the 10-fold
lower affinity of the rSULT1C1 variant enzyme for 3,3'-T2
compared with the wild-type rSULT1C1. Previous studies showed that hSULT1A1
efficiently sulfates iodothyronines, whereas the rSULT1A1 homolog does not
catalyze iodothyronine sulfation
(44). The human estrogen
sulfotransferase hSULT1E1 also efficiently catalyzes iodothyronine sulfation
(24). However, because estrone
and estradiol are inefficient substrates for the rat homolog rSULT1E1
(10), it is not surprising
that no catalytic activity toward iodothyronines was detected for this enzyme.
Still, iodothyronine sulfation by rSULT1E2 is not excluded. In rats as well as
in humans (Kester MHA, Coughtrie MWH, Glatt H, and Visser TJ, unpublished
observations), hydroxysteroid sulfotransferases do not appear to contribute
importantly to iodothyronine sulfation.
Because all enzymes prefer 3,3'-T2 as substrate, in this
study we have used 3,3'-T2 as the model substrate for the
receptor-active T3. Physiologically, T3 is perhaps the
most important substrate, since sulfation is an important pathway for the
inactivation of the hormone. However, a physiological role for
3,3'-T2 cannot be excluded. The diiodothyronines
3,3'-T2 and 3,5-T2 have been shown to stimulate
mitochondrial thermogenesis by direct mitochondrial binding
(31a). Furthermore, Wu et al.
(46) showed that, in late
gestation in sheep, 3,3'-T2 sulfate is the most abundant
iodothyronine metabolite transferred from the fetus to the mother. Possibly,
sulfation of 3,3'-T2 and the transfer of
3,3'-T2 sulfate from fetus to mother protects the fetus from
excessive mitochondrial respiration.
In conclusion, rSULT1B1 and -1C1 appear to be important enzyme forms for
sulfation of iodothyronines in rat liver and kidney, with proportionally
greater contributions in kidney than in liver and in male than in female
liver. Other, still unidentified enzymes appear to be responsible for
iodothyronine sulfation in rat brain. Further studies are needed to determine
the role of these sulfotransferases in the regulation of (fetal) thyroid
hormone status.
 |
DISCLOSURES
|
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This work was supported by the Sophia Foundation for Medical Research
(Project no. 211), by European Community Grants BMH1-CT92-0097 and
QLG-2000-00930, and by the Netherlands Organization for Scientific Research
Grant 903-40-204.
 |
ACKNOWLEDGMENTS
|
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We thank Dr. Y. Yamazoe and Dr. C. N. Falany for generous gifts of the
rSULT1A1 and 1C1 cDNA clones.
 |
FOOTNOTES
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Address for reprint requests and other correspondence: T. J. Visser, Dept. of
Internal Medicine, Erasmus Medical Center, Rm. Ee 502, Dr Molewaterplein 50,
3015 GE Rotterdam, The Netherlands (E-mail address:
t.j.visser{at}erasmusmc.nl).
The costs of publication of this article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section 1734
solely to indicate this fact.
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