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Medical Research Council Group in Molecular Endocrinology, CHUL Research Center and Laval University, Québec, Canada G1V 4G2
Address all correspondence and requests for reprints to: Dr. Van Luu-The, Medical Research Council Group in Molecular Endocrinology, CHUL Research Center, 2705 Laurier Boulevard, Québec, Québec, Canada G1V 4G2.
17ß-Hydroxysteroid dehydrogenases (17ßHSDs) play an essential role
in the formation of active intracellular sex steroids. Six types of
17ßHSD have been described to date, which only share approximately
20% homology. Human type 5 17ßHSD complementary DNA is unique among
the 17ßHSDs because it belongs to the aldo-keto reductase family,
whereas the others are members of the short chain alcohol
dehydrogenases. The characteristics of human type 5 17ßHSD were
investigated in human embryonic (293) cells stably transfected with
human and mouse type 5 17ßHSD, as well as human type 3 3
HSD. Using
intact transfected cells, type 5 17ßHSD shows a substrate specificity
pattern comparable to those of human type 3 17ßHSD and mouse type 5
17ßHSD. These enzymes catalyze more efficiently the transformation of
androstenedione (4-dione) to testosterone, whereas the transformation
of dihydrotestosterone to 5-androstane-3,17ß-diol is much
lower. In contrast, type 3 3HSD catalyzes more efficiently the
transformation of dihydrotestosterone to
5-androstane-3,17ß-diol, whereas the transformation of 4-dione
to testosterone represents only 7% of the 3HSD activity. However,
upon homogenization, human type 5 17ßHSD activity decreases to
approximately 10% of the activity in intact cells and remains stable
at this level together with the 3HSD activity. Under the same
conditions, however, the mouse enzyme is not altered by homogenization.
Indeed, using purified human 17ßHSD overexpressed in
Escherichia coli, we could confirm that a much greater
amount of protein is required to produce activity similar to the
enzymatic activity measured in intact transfected cells. The present
data provide the answer to the question of why previous researchers
could hardly detect type 5 17ßHSD activity. Indeed, all previous
publications used cell or tissue homogenates or purified enzymes. Under
such conditions, only the low level, but stable, 3HSD and 17ßHSD
activities could be measured, whereas the high level, but highly
unstable, 17ßHSD activity could not be measured. As type 5 17ßHSD
shares 84%, 86%, and 88% amino acid identity with types 1 and 3
3HSD and 20HSDs, respectively, Northern blot analysis used in
previous studies could not provide unequivocal information. In this
report, we used a more specific ribonuclease protection assay and could
thus show that human type 5 17ßHSD is expressed in the liver,
adrenal, and prostate; in prostatic cancer cell lines DU-145 and LNCaP;
as well as in bone carcinoma (MG-63) cells. By analogy with type 3
17ßHSD, which is responsible for the formation of androgens in the
testis, the expression of type 5 17ßHSD in the prostate and bone
cells suggests that this enzyme is involved in the formation of active
intracellular androgens in these tissues.
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S. Steckelbroeck, M. Watzka, R. Reichelt, V. H. J. Hans, B. Stoffel-Wagner, D. D. Heidrich, J. Schramm, F. Bidlingmaier, and D. Klingmüller Characterization of the 5{{alpha}}-Reductase-3{{alpha}}-Hydroxysteroid Dehydrogenase Complex in the Human Brain J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1324 - 1331. [Abstract] [Full Text]
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I. Dufort, F. Labrie, and V. Luu-The Human Types 1 and 3 3{{alpha}}-Hydroxysteroid Dehydrogenases: Differential Lability and Tissue Distribution J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 841 - 846. [Abstract] [Full Text]
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B. Lin, J. T. White, C. Ferguson, S. Wang, R. Vessella, R. Bumgarner, L. D. True, L. Hood, and P. S. Nelson Prostate Short-Chain Dehydrogenase Reductase 1 (PSDR1): A New Member of the Short-Chain Steroid Dehydrogenase/Reductase Family Highly Expressed in Normal and Neoplastic Prostate Epithelium Cancer Res., February 1, 2001; 61(4): 1611 - 1618. [Abstract] [Full Text]
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P. R. Provost, C. H. Blomquist, C. Godin, X.-F. Huang, N. Flamand, V. Luu-The, D. Nadeau, and Y. Tremblay Androgen Formation and Metabolism in the Pulmonary Epithelial Cell Line A549: Expression of 17{beta}-Hydroxysteroid Dehydrogenase Type 5 and 3{alpha}-Hydroxysteroid Dehydrogenase Type 3 Endocrinology, August 1, 2000; 141(8): 2786 - 2794. [Abstract] [Full Text] [PDF]
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P. J. O'Shaughnessy, P. J. Baker, M. Heikkila, S. Vainio, and A. P. McMahon Localization of 17{beta}-Hydroxysteroid Dehydrogenase/17-Ketosteroid Reductase Isoform Expression in the Developing Mouse Testis--Androstenedione Is the Major Androgen Secreted by Fetal/Neonatal Leydig Cells Endocrinology, July 1, 2000; 141(7): 2631 - 2637. [Abstract] [Full Text] [PDF]
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 P. A. Thompson and C. Ambrosone Chapter 7: Molecular Epidemiology of Genetic Polymorphisms in Estrogen Metabolizing Enzymes in Human Breast Cancer J Natl Cancer Inst Monographs, July 1, 2000; 2000(27): 125 - 134. [Abstract] [Full Text] [PDF]
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New Insight into the Molecular Basis of 3{beta}-Hydroxysteroid Dehydrogenase Deficiency: Identification of Eight Mutations in the HSD3B2 Gene in Eleven Patients from Seven New Families and Comparison of the Functional Properties of Twenty-Five Mutant Enzymes J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4410 - 4425. [Abstract] [Full Text]
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S. Gingras and J. Simard Induction of 3{beta}-Hydroxysteroid Dehydrogenase/ Isomerase Type 1 Expression by Interleukin-4 in Human Normal Prostate Epithelial Cells, Immortalized Keratinocytes, Colon, and Cervix Cancer Cell Lines Endocrinology, October 1, 1999; 140(10): 4573 - 4584. [Abstract] [Full Text]
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M. A. English, K. F. Kane, N. Cruickshank, M. J. S. Langman, P. M. Stewart, and M. Hewison Loss of Estrogen Inactivation in Colonic Cancer J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 2080 - 2085. [Abstract] [Full Text]
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X.-F. Huang and V. Luu-The Molecular Characterization of a First Human 3(alpha right-arrowbeta )-Hydroxysteroid Epimerase J. Biol. Chem., September 15, 2000; 275(38): 29452 - 29457. [Abstract] [Full Text] [PDF]
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R. Zheng, T. S. A. Samy, C. P. Schneider, L. W. Rue III, K. I. Bland, and I. H. Chaudry Decreased 5alpha -dihydrotestosterone catabolism suppresses T lymphocyte functions in males after trauma-hemorrhage Am J Physiol Cell Physiol, June 1, 2002; 282(6): C1332 - C1338. [Abstract] [Full Text] [PDF]
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