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Original Studies |
Oncology and Molecular Endocrinology Research Center, Medical Research Council Group in Molecular Endocrinology (A.B.), CHUL Research Center, Laval University, Quebec, Canada G1V 4G2
Address all correspondence and requests for reprints to: Dr. Alain Bélanger, Oncology and Molecular Endocrinology Research Center, CHUL Research Center, 2705 Laurier Boulevard, Quebec, Canada G1V 4G2. E-mail: alain.belanger{at}crchul.ulaval.ca
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-diol glucuronide, thus suggesting an important role of UGT2B
enzymes in androgen metabolism. To investigate the cellular
localization of UGT2B expression in the human prostate, the present
in situ hybridization studies demonstrated the presence
of UGT2B transcripts in epithelial cells lining the acinii. All basal
cells were intensively labeled, whereas the luminal secretory cells
were moderately labeled. To confirm these results, an
immunohistological analysis was performed using a specific anti-UGT2B
antibody. The presence of UGT2B proteins was observed in both basal and
luminal cells of prostate epithelium, in fibrocytes of stroma and blood
vessels, and in endothelial cells of blood vessels. Using a specific
anti-UGT2B17 antibody, the expression of this androsterone-conjugating
UGT enzyme was found exclusively in basal cells of the epithelium.
These results demonstrate the expression of androgen-conjugating UGT2B
enzymes in human prostatic epithelium. Moreover, they show for the
first time a cell type-specific expression of an UGT2B isoform. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To date, more than 61 different UGT complementary DNA (cDNA) clones
from six mammalian species have been isolated (3, 4).
Based on the homology of protein primary structure, they have been
categorized into two major families, UGT1 and UGT2 (3).
Enzymes of the UGT2 family were further divided into three subfamilies:
UGT2A, UGT2B, and UGT2C. To date three UGT2A cDNAs have been described.
UGT2A1 in the rat, bovine, and human is expressed in the olfactive
epithelium (3, 5, 6). It has been proposed that the
mechanism of sensory perception uses glucuronidation as a means to
rapidly inactivate an odorant molecule, thus indicating that UGT
enzymes provide an effective mechanism of signal termination
(5). Only one UGT2C cDNA has been cloned from rabbit with
a still unknown function (7). Six human UGT2B enzymes have
been characterized to date, with two of them (UGT2B10 and UGT2B11)
demonstrating no UGT activity (8, 9), whereas human
UGT2B4, UGT2B7, UGT2B15, and UGT2B17 have been shown to catalyze the
glucuronidation of bile acids, steroids, fatty acids, carboxylic acids,
phenols, and/or carcinogens (9, 10, 11, 12, 13). Despite their large
substrate specificity, it is known that UGT2B enzymes are more specific
for C19 steroid glucuronidation [mainly
dihydrotestosterone (DHT), androsterone (ADT), and
androstane-3,17ß-diol (3-Diol)] (4, 14). Each
UGT2B protein is encoded by a separated gene, and recent studies
suggested that the UGT2B4, UGT2B15, and UGT2B17
genes are clustered in the region 4q13–4q21.1
(15, 16, 17, 18).
Several studies suggested that the serum levels of androgens are poor
indicators of total androgenic activity in human steroid target tissues
(19), whereas levels of circulating conjugated androgen
metabolites were shown to be correlated with the total androgen pool in
men (19). In addition, plasma levels of steroid
glucuronides are increased in specific hyperandrogenic pathologies such
as acne or hirsutism, both associated with an increased production of
5-reduced C19 steroids (20).
Although it is generally accepted that the liver is an important site
of glucuronidation, specific RT-PCR studies have shown that other
tissues, such as prostate, testis, kidney, and breast, express
steroid-conjugating UGT2B transcripts (4). Thus,
expression of all cloned UGT2B transcripts, with the exception of
UGT2B7, was demonstrated in human prostate (4). On the
other hand, androgens play an essential role in prostate development,
growth, and function. Human prostate synthesizes its own androgens,
namely testosterone and DHT, from circulating dehydroepiandrosterone
and its sulfate (21). In addition, formation of androgen
glucuronides, ADT glucuronide (ADT-G) and 3-Diol glucuronide
(3-Diol-G), in human prostate has been well documented
(22). Depending on their substrate specificity, it is
apparent that the expression of each UGT2B protein in the human
prostate might play a critical role in androgen catabolism.
Recently, El-Alfy et al., demonstrated the expression of 17ß-hydroxysteroid dehydrogenase (17ßHSD) type 5 and 3ßHSD in the basal cells of the human prostate epithelium, whereas the androgen receptor was localized mainly in the nuclei of luminal cells (23). A two-cell mechanism of androgen synthesis in the human prostate was proposed. This model suggests that testosterone and DHT could be formed in the basal cells from the dehydroepiandrosterone secreted by the adrenal gland. Then, testosterone from the circulation and from basal cells and DHT formed in basal cells can diffuse into the luminal cells, where they serve as ligand for the androgen receptor (23). To further understand the role of UGT2B enzymes in the catabolism of androgen in prostatic target cells and to determine their potential as effective hormonal signal terminators, we analyzed their cellular localization using in situ hybridization and immunohistochemistry approaches.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Restriction enzymes and other molecular biology reagents were
obtained from Stratagene (La Jolla, CA), Pharmacia
LKB Biotechnology, Inc. (Milwaukee, WI), Life Technologies, Inc. (Ontario, Canada), and Roche Molecular Biochemicals (Indianapolis, IN). Protein assay reagents were
obtained from Bio-Rad Laboratories, Inc. (Richmond, CA).
[-32P]Deoxy-CTP (3000 Ci/mmol) and
[3H]UTP were obtained from NEN Life Science Products-DuPont (Boston, MA). The Riboprobe R
Gemini II kit was purchased from Promega Corp. (Madison,
WI), and the immunohistochemical kit (Vectastain ABC kit)
was obtained from Vector Laboratories, Inc. (Burlingame,
CA).
Tissue preparation
Adult prostatic tissue was obtained from six patients with symptomatic benign prostatic hyperplasia who were undergoing transurethral prostatectomy (23). For in situ hybridization, two specimens were fixed by immersion in 2% glutaraldehyde, 4% formaldehyde, and 3% dextran in 0.05 mol/L phosphate buffer (pH 7.4). The four remaining prostate samples were fixed in 4% formaldehyde for immunohistochemistry analysis. After 4 h, all specimens were processed and embedded in paraffin. Histological analysis of these tissues revealed parts with normal epithelium and stroma, which were used for in situ hybridization and immunohistochemical studies.
Subcloning of the UGT2B probe and Southern blot analysis
Sequencing of numerous mammalian UGT2B proteins demonstrated
that their carboxyl-terminal domain (amino acids 291–530) is highly
conserved. This amino acid identity reflect the high homology of the
3'-end translated region of UGT2B cDNAs. Based on this characteristic,
the monkey UGT2B20 445-bp cDNA EcoRI-SacI
fragment was subcloned in the phagemid pBluescript. This fragment was
used for complementary ribonucleic acid (cRNA) probe synthesis, with a
predicted binding domain composed of coding nucleic acids from 912-1357
of all human cDNAs. The entire UGT2B4, UGT2B7, UGT2B10, UGT2B15, and
UGT2B17 cDNAs were electrophoresed on a 1% agarose gel and transferred
onto a nylon membrane for Southern blot analysis. The blot was
prehybridized in 50% formamide, 5 x Denhardt’s, 6 x SSC
(standard saline citrate), 50 mmol/L Tris (pH 8.0), 1% SDS, and 100
µg/mL salmon sperm DNA for 5 h at 42 C. Hybridization was
performed with 1.5 x 106 cpm/mL of the
[-32P]deoxy-CTP-UGT2B probe in the same
buffer as prehybridization for 16 h at 42 C. The blot was washed
twice in 0.1% SDS-2 x SSC at 65 C for 30 min and exposed on XAR5
film with an intensifying screen (Eastman Kodak Co.,
Rochester, NY) for 16 h.
Characterization of anti-UGT2B EL-93 and anti-UGT2B17 EL-95 antibodies
As previously described (24), anti-UGT2B EL-93 and anti-UGT2B17 EL-95 antibodies were raised against a 29-kDa fragment of the UGT2B17 protein. This fragment, composed of amino acids 57–300, corresponds to the portion of the UGT2B17 protein that is the least homologous to other human UGT2B. Several rabbits were injected with a total of 100 µg purified fusion proteins in the presence of incomplete Freund’s adjuvant. The production of antibody was determined 12 days after the injections. To gain information concerning the novel anti-UGT2B antibodies, Western blot experiments using the recombinant UGT2B17 protein fragment and microsomal proteins from UGT2B15- and UGT2B17-HK293 cells showed that the immune serum EL-93 binds both proteins, whereas the immune serum EL-95 recognized specifically the UGT2B17 protein (Lévesque, E., et al., unpublished results) (24). The antisera EL-93 and EL-95 were then designated anti-UGT2B EL-93 antibody and anti-UGT2B17 EL-95 antibody, respectively.
However, in the present study we determined the ability of these antibodies to recognize human UGT proteins using immunoblot analysis. The isolation of human UGT2B cDNAs and their stable expression in human kidney 293 (HK293) cells have been described previously (9, 10, 11, 12, 13). Microsomal proteins were isolated by differential centrifugation. In brief, HK293 cells and cells stably expressing UGT1A and UGT2B proteins were resuspended in 10 mmol/L Tris buffer saline containing 0.5 mmol/L dithiothreitol, centrifuged at 14,000 rpm for 5 min, resuspended in homogenization buffer, and frozen at -80 C until microsome isolation. The homogenization was performed in 0.1 mol/L K2HPO4, 0.1 mol/L KH2PO4 (pH 7.4), 20% glycerol, 1 mmol/L ethylenediamine tetraacetate, 1 mmol/L dithiothreitol, 2.5 µg/mL pepstatin, and 0.5 µg/mL leupeptin using a Potter-Glas-Col (Terre Haute, IN) homogenizer with a Teflon pestle. The resulting homogenates were centrifuged at 12,000 x g at 4 C for 20 min. The supernatant was then centrifuged at 105,000 x g for 1 h at 4 C. The microsomal pellets were resuspended in 0.5 mL homogenization buffer and stored at -80 C.
Microsomal proteins (10 µg) of HK293 cells and HK293 cells stably expressing UGT1A1, UGT1A3, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B10, UGT2B15, and UGT2B17 were separated by 10% SDS-PAGE. The gels were transferred onto nitrocellulose membranes and incubated with anti-UGT2B EL-93 or anti-UGT2B17 EL-95 antibodies (dilution, 1:2000) as previously described (24). An antirabbit IgG antibody conjugated with peroxidase (Amersham Pharmacia Biotech, Ontario, Canada) was used as the second antibody, and the resulting immunocomplexes were visualized using a chemiluminescence kit (ECL, Renaissance, Quebec, Canada) and exposed on Hyperfilm for 4 min (Kodak).
Riboprobe synthesis and in situ hybridization analysis
Riboprobes were generated by in vitro transcription from the pBluescript phagemid containing the UGT2B fragment. Using T3 and T7 RNA polymerases, respectively, sense and antisense cRNAs were generated in the presence of [3H]UTP (NEN Life Science Products-DuPont) with the Riboprobe R Gemini II as indicated by the supplier (Promega Corp.). Thick paraffin sections (20 µm) of the two human prostate specimens were cut, and the floating section was deparaffinized in toluene. All sections were subsequently rehydrated; postfixed in 2% glutaraldehyde, 4% formaldehyde, and 3% dextran in 0.05 mol/L phosphate buffer; and washed in the same buffer containing 7.5% glycine. Hybridization of the floating sections was performed overnight at 40 C with [3H]UTP riboprobes. After hybridization, sections were postfixed in osmium tetroxide, flat-embedded in Epon, and cut at 0.7 µm with an ultramicrotome. Sections were first stained and then coated with liquid photographic emulsion (Kodak NTB2) and developed after 28 days of exposure.
Immunohistochemistry analysis
Four-micron paraffin sections from four different human
prostates were mounted on glass slides, deparaffinized using toluene,
and then rehydrated. Immunostaining was performed using anti-UGT2B
EL-93 or anti-UGT2B17 EL-95 antisera diluted 1:200 in Tris saline, pH
7.6, for 1 h at room temperature. Sections were subsequently
washed with phosphate-buffered saline and incubated with a
biotin-labeled goat antirabbit 
-globulin diluted 1:1500 for 10 min.
After incubation, the sections were treated with streptavidin coupled
with peroxidase, and diaminobenzidine was used as the chromogen to
visualize the biotin-streptavidin-peroxidase complex (Vectastain ABC
kit, Vector Laboratories, Inc.) after exposition of 2 min.
Endogenous peroxidase activity was eliminated by preincubation with 3%
H2O2 for 20 min. The
intensity of the staining was controlled under the microscope. The
sections were then counterstained with hematoxylin. Control experiments
were performed on consecutive sections using preimmune rabbit serum
(1:100).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine the ability of the 445-bp UGT2B probe to bind human
UGT2B transcripts, a Southern blot analysis was performed using human
UGT2B cDNAs (Fig. 1
). The results
demonstrated that the UGT2B probe, which has high nucleotide sequence
identity with the human cDNAs of UGT2B4, UGT2B7, and UGT2B10 (87%
nucleic acid identity) and UGT2B15 and UGT2B17 (97% nucleic acid
identity), can specifically bind to coding nucleic acids 912-1357 of
all human UGT2B transcripts.
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Two antibodies, anti-UGT2B EL-93 and anti-UGT2B17 EL-95, were
previously obtained using a 29-kDa fragment of the UGT2B17 protein
(24). The specificity of the two antisera was examined by
immunoblot analysis, using microsomal proteins (10 µg) of HK293 cells
stably expressing UGT1A1, UGT1A3, UGT1A6, UGT1A9, UGT2B4, UGT2B7,
UGT2B10, UGT2B15, and UGT2B17. Although the anti-UGT2B EL-93 antibody
recognized all five UGT2B enzymes (Fig. 2A), the anti-UGT2B17 EL-95 antibody was
significantly more specific in preferentially binding UGT2B17 protein
(Fig. 2B). In both experiments, no protein was detected in
untransfected HK293 cells, thus demonstrating the specificities of
these antibodies. When using the anti-UGT2B EL-93 antibody, the
difference in staining corresponded to different levels of UGT2B
protein expression in each cell line. As expected, neither antibody
bound UGT1A proteins (Fig. 2, C and D), thus demonstrating their
specificities for UGT proteins of the 2B subfamily.
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Using the 3H-labeled UGT2B probe for the
in situ hybridization analysis, UGT2B transcripts were
detected in epithelial cells of the two prostate specimens analyzed
(Fig. 3a). Although all basal and luminal
cells were labeled, the intensity of the signal was significantly more
intense in basal cells than in luminal cells. When the hybridization
was performed using 3H-labeled sense riboprobe as
a negative control, only a few scattered silver grains were detected
over the epithelium (Fig. 3b).
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). Interestingly,
few white blood cells presented labeling, indicating the presence of
UGT2B transcripts (Fig. 3c). Immunostaining
Using the anti-UGT2B EL-93 antibody, protein expression was found
in all basal and luminal cells (Fig. 4, a
and b). UGT2B proteins were distributed mainly in the cytoplasm of
epithelial cells; few nuclei were stained. As observed with in
situ hybridization, the staining was stronger in basal cells than
in luminal cells (Fig. 4). Interestingly, the specific anti-UGT2B17
EL-95 antibody yielded staining exclusively in basal cells of the
prostate epithelium (Fig. 4, c and d), indicating that this enzyme is
expressed only in these cells and not in the luminal layer. When the
preimmune serum was used, no staining could be detected (Fig. 4e).
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). Some smooth muscle cells of the
tunica media and most of the fibrocytes in the tunica adventitia of
arteries were stained (Fig. 5a). In the wall of veins, fibroblasts
appeared well labeled (Fig. 5b). As in the epithelium, the preimmune
serum did not produce staining reaction, indicating the specificity of
the results obtained with the antisera (Fig. 5c).
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). As previously,
the preimmune serum shared no reaction (Fig. 5e). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To date, six human UGT2B enzymes have been characterized and the
transferase activity of UGT2B4, UGT2B7, UGT2B15, and UGT2B17 was
previously shown on several steroid substrates (4).
Although UGT2B15 catalyzes specifically the glucuronidation of
17ß-hydroxyandrogens (DHT, testosterone, and 3-Diol), UGT2B7 and
UGT2B17 are involved in the transfer of glucuronosyl group on both
3- and 17ß-hydroxypositions of C19 steroids
(10, 11, 12). Human UGT2B4 is primarily involved in bile acids
and catechol estrogens conjugation; however, a slight glucuronidation
activity of this isoform was reported toward ADT and 3-Diol
(13, 26, 27, 28). Tissue distribution analysis of UGT2B
transcripts demonstrated their presence in several human tissues. In
the prostate, specific RT-PCR experiments have shown the presence of
messenger RNAs (mRNAs) corresponding to UGT2B4, UGT2B15, and UGT2B17,
whereas the presence of UGT2B7 was not observed (4). In
the present study we used two complementary approaches, namely in
situ hybridization and immunohistochemistry, to identify specific
cells that expressed UGT2B enzymes in the human prostate. These
proteins were found in both basal and luminal cells of the tube
alveoli, in fibroblasts of stroma and blood vessels, and in the
endothelial cells of blood vessels. This double approach permits us to
identify not only the UGT2B transcripts, but also the enzymes
themselves.
In human prostate, the stratified columnar epithelium lining the
tube-alveoli is divided into two layers, namely the basal layer (low
cuboidal cells) and the luminal layer (columnar secretory cells).
Previous studies have analyzed the prostatic cellular expression of
enzymes involved in androgen biosynthesis and catabolism. For example,
it was reported that the 5-reductase type I enzyme was expressed
mainly in basal cells, whereas a low level of this protein was detected
in luminal cells (29). However, the two enzymes 3ßHSD
and 17ßHSD type 5 are expressed only in basal cells
(23), whereas the presence of androgen receptor only in
luminal cells has been clearly established in several studies
(30, 31, 32). The expression of 3HSD enzyme was poorly
investigated, but preliminary results suggest the presence of the
3HSD type III in basal layer of human prostate epithelium (El Alfy,
M., et al., personal communication). All of these data
clearly suggested a two-cell mechanism of androgen formation and
action. In basal cells, testosterone come from circulation or is formed
by reduction of the 4-ene-dione by 17ßHSD type 5 (Fig. 6). In these cells, the reduction of
testosterone into DHT is made possible by the presence of
5-reductase. Then, DHT and/or testosterone can diffuse to luminal
cells and bind to the androgen receptor. However, it is apparent that
5-reductase enzyme is also, although significantly less, expressed
in luminal cells, suggesting a possible formation of DHT in this cell
type (Fig. 6) (23).
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). In addition, according to its catalytic
activity profile, UGT2B15 could be involved in the elimination of
excess testosterone diffusing from the basal layer. In basal cells, the
presence of the UGT2B17 enzyme (and of UGT2B4 at a lower level) could
be responsible for the formation of 3-Diol-G and ADT-G. The
5-reduced metabolites 3-diol and ADT are formed both from
androstanedione or DHT by the way of 3HSD and 17ßHSD. In these
cells, UGT2B17 could also glucuronidate 3-Diol, and the remaining
DHT and testosterone (Fig. 6).
Fibroblasts present in the stroma as well as those associated with the
blood vessels are shown to contain UGT2B mRNAs and immunoreactive
proteins. Although the role of the conjugating enzymes in fibroblasts
remains to be established, this observation is in agreement with
previous studies that have demonstrated the presence of 17ßHSD,
3ßHSD, and 5-reductase in this cell type (23, 29). In
addition, androgen receptor was also shown to be present in the nuclei
of most stromal cells (23), suggesting an active role of
androgens in fibroblast development and function.
An interesting observation of the present study is the localization of
UGT2B transcripts and proteins in blood vessel wall and of UGT2B
transcripts in some blood cells. As in stromal cells, previous studies
have demonstrated the presence of 5-reductase, 3ßHSD, and 17ßHSD
in endothelial cells of blood vessels (23). Although the
role of steroidogenic enzymes in these vascular structures is unknown,
the presence of UGT2B enzymes suggest a metabolic process for androgen
elimination.
The results of the present study demonstrate the presence of UGT2B transcripts and proteins in steroidogenic prostatic cells. Moreover, for the first time, evidence of cell type-specific expression of UGT2B isoenzymes has also been obtained. Finally, the presence of UGT2B proteins in androgen target cells illustrates their major roles in cellular metabolism of androgens and suggest that UGT2B enzymes provide an effective mechanism of hormonal signal termination.
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Acknowledgments |
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Footnotes |
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Received April 28, 2000.
Revised August 15, 2000.
Accepted August 25, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-reduced steroid glucuronides in
hyperandrogenic and idiopathic hirsute women. Fertil Steril. 48:948–953.[Medline]
-reductase 2 with polyclonal antibodies in androgen target and
non-target human tissues. J Histochem Cytochem. 42:667–675.[Abstract]
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