Abstract
17beta-Hydroxysteroid dehydrogenases (17HSDs) are responsible for the conversion of low-activity sex steroids to more potent forms, and vice versa. 17HSD activity is essential for the biosynthesis of sex steroids in the gonads, and it is also one of the key factors regulating the availability of active ligands for sex-steroid receptors in various extragonadal tissues. In this study, we have characterized mouse 17HSD type 2 cDNA, and analysed the relative expression of 17HSD types 1, 2, 3, 4 and 5 mRNAs in mouse embryos and adult male and female tissues. The cDNA characterized has a open reading frame of 1146 bp, and encodes a protein of 381 amino acids with a predicted molecular mass of 41837 kDa. Northern-blot analysis of adult mouse tissues revealed that, of the different 17HSDs, the type 2 enzyme is most abundantly expressed. High expression of the enzyme, which oxidizes both testosterone and oestradiol, in several large organs of both sexes indicates that it is the isoform having the most substantial role in the metabolism of sex steroids. Interestingly, four of the five 17HSD enzymes were also detected by Northern blots of whole mouse embryos, and each of the enzymes showed a unique pattern of expression. The oestradiol-synthesizing type 1 enzyme predominates in early days of development embryonic day 7, but after that the oxidative type 2 enzyme becomes the predominant form of all 17HSDs. The data therefore suggest that there is transient oestradiol production in the early days of embryonic development, after which inactivation of sex steroids predominates in the fetus and placenta.
Full Text
The Full Text of this article is available as a PDF (697.5 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Adamski J., Normand T., Leenders F., Monté D., Begue A., Stéhelin D., Jungblut P. W., de Launoit Y. Molecular cloning of a novel widely expressed human 80 kDa 17 beta-hydroxysteroid dehydrogenase IV. Biochem J. 1995 Oct 15;311(Pt 2):437–443. doi: 10.1042/bj3110437. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Akinola L. A., Poutanen M., Vihko R. Cloning of rat 17 beta-hydroxysteroid dehydrogenase type 2 and characterization of tissue distribution and catalytic activity of rat type 1 and type 2 enzymes. Endocrinology. 1996 May;137(5):1572–1579. doi: 10.1210/endo.137.5.8612487. [DOI] [PubMed] [Google Scholar]
- Andersson S., Geissler W. M., Wu L., Davis D. L., Grumbach M. M., New M. I., Schwarz H. P., Blethen S. L., Mendonca B. B., Bloise W. Molecular genetics and pathophysiology of 17 beta-hydroxysteroid dehydrogenase 3 deficiency. J Clin Endocrinol Metab. 1996 Jan;81(1):130–136. doi: 10.1210/jcem.81.1.8550739. [DOI] [PubMed] [Google Scholar]
- Baker M. E. Unusual evolution of 11beta- and 17beta-hydroxysteroid and retinol dehydrogenases. Bioessays. 1996 Jan;18(1):63–70. doi: 10.1002/bies.950180112. [DOI] [PubMed] [Google Scholar]
- Casey M. L., MacDonald P. C., Andersson S. 17 beta-Hydroxysteroid dehydrogenase type 2: chromosomal assignment and progestin regulation of gene expression in human endometrium. J Clin Invest. 1994 Nov;94(5):2135–2141. doi: 10.1172/JCI117569. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Conley A. J., Christenson L. K., Ford S. P., Christenson R. K. Immunocytochemical localization of cytochromes P450 17 alpha-hydroxylase and aromatase in embryonic cell layers of elongating porcine blastocysts. Endocrinology. 1994 Dec;135(6):2248–2254. doi: 10.1210/endo.135.6.7988410. [DOI] [PubMed] [Google Scholar]
- Deyashiki Y., Ohshima K., Nakanishi M., Sato K., Matsuura K., Hara A. Molecular cloning and characterization of mouse estradiol 17 beta-dehydrogenase (A-specific), a member of the aldoketoreductase family. J Biol Chem. 1995 May 5;270(18):10461–10467. doi: 10.1074/jbc.270.18.10461. [DOI] [PubMed] [Google Scholar]
- Dieuaide-Noubhani M., Novikov D., Baumgart E., Vanhooren J. C., Fransen M., Goethals M., Vandekerckhove J., Van Veldhoven P. P., Mannaerts G. P. Further characterization of the peroxisomal 3-hydroxyacyl-CoA dehydrogenases from rat liver. Relationship between the different dehydrogenases and evidence that fatty acids and the C27 bile acids di- and tri-hydroxycoprostanic acids are metabolized by separate multifunctional proteins. Eur J Biochem. 1996 Sep 15;240(3):660–666. doi: 10.1111/j.1432-1033.1996.0660h.x. [DOI] [PubMed] [Google Scholar]
- Geissler W. M., Davis D. L., Wu L., Bradshaw K. D., Patel S., Mendonca B. B., Elliston K. O., Wilson J. D., Russell D. W., Andersson S. Male pseudohermaphroditism caused by mutations of testicular 17 beta-hydroxysteroid dehydrogenase 3. Nat Genet. 1994 May;7(1):34–39. doi: 10.1038/ng0594-34. [DOI] [PubMed] [Google Scholar]
- George F. W., Wilson J. D. Estrogen formation in the early rabbit embryo. Science. 1978 Jan 13;199(4325):200–201. doi: 10.1126/science.579477. [DOI] [PubMed] [Google Scholar]
- Ghersevich S., Poutanen M., Tapanainen J., Vihko R. Hormonal regulation of rat 17 beta-hydroxysteroid dehydrogenase type 1 in cultured rat granulosa cells: effects of recombinant follicle-stimulating hormone, estrogens, androgens, and epidermal growth factor. Endocrinology. 1994 Nov;135(5):1963–1971. doi: 10.1210/endo.135.5.7956918. [DOI] [PubMed] [Google Scholar]
- Lacy W. R., Washenick K. J., Cook R. G., Dunbar B. S. Molecular cloning and expression of an abundant rabbit ovarian protein with 20 alpha-hydroxysteroid dehydrogenase activity. Mol Endocrinol. 1993 Jan;7(1):58–66. doi: 10.1210/mend.7.1.8446108. [DOI] [PubMed] [Google Scholar]
- Leenders F., Adamski J., Husen B., Thole H. H., Jungblut P. W. Molecular cloning and amino acid sequence of the porcine 17 beta-estradiol dehydrogenase. Eur J Biochem. 1994 May 15;222(1):221–227. doi: 10.1111/j.1432-1033.1994.tb18860.x. [DOI] [PubMed] [Google Scholar]
- Leenders F., Tesdorpf J. G., Markus M., Engel T., Seedorf U., Adamski J. Porcine 80-kDa protein reveals intrinsic 17 beta-hydroxysteroid dehydrogenase, fatty acyl-CoA-hydratase/dehydrogenase, and sterol transfer activities. J Biol Chem. 1996 Mar 8;271(10):5438–5442. doi: 10.1074/jbc.271.10.5438. [DOI] [PubMed] [Google Scholar]
- Markus M., Husen B., Adamski J. The subcellular localization of 17 beta-hydroxysteroid dehydrogenase type 4 and its interaction with actin. J Steroid Biochem Mol Biol. 1995 Dec;55(5-6):617–621. doi: 10.1016/0960-0760(95)00213-8. [DOI] [PubMed] [Google Scholar]
- Martel C., Rhéaume E., Takahashi M., Trudel C., Couët J., Luu-The V., Simard J., Labrie F. Distribution of 17 beta-hydroxysteroid dehydrogenase gene expression and activity in rat and human tissues. J Steroid Biochem Mol Biol. 1992 Mar;41(3-8):597–603. doi: 10.1016/0960-0760(92)90390-5. [DOI] [PubMed] [Google Scholar]
- Miettinen M. M., Mustonen M. V., Poutanen M. H., Isomaa V. V., Vihko R. K. Human 17 beta-hydroxysteroid dehydrogenase type 1 and type 2 isoenzymes have opposite activities in cultured cells and characteristic cell- and tissue-specific expression. Biochem J. 1996 Mar 15;314(Pt 3):839–845. doi: 10.1042/bj3140839. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Milewich L., Garcia R. L., Gerrity L. W. 17 beta-Hydroxysteroid oxidoreductase: a ubiquitous enzyme. Interconversion of estrone and estradiol-17 beta in BALB/c mouse tissues. Metabolism. 1985 Oct;34(10):938–944. doi: 10.1016/0026-0495(85)90142-8. [DOI] [PubMed] [Google Scholar]
- Milewich L., MacDonald P. C., Carr B. R. Activity of 17 beta-hydroxysteroid oxidoreductase in tissues of the human fetus. J Endocrinol. 1989 Dec;123(3):509–518. doi: 10.1677/joe.0.1230509. [DOI] [PubMed] [Google Scholar]
- Miura R., Shiota K., Noda K., Yagi S., Ogawa T., Takahashi M. Molecular cloning of cDNA for rat ovarian 20 alpha-hydroxysteroid dehydrogenase (HSD1). Biochem J. 1994 Apr 15;299(Pt 2):561–567. doi: 10.1042/bj2990561. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nilsson T., Warren G. Retention and retrieval in the endoplasmic reticulum and the Golgi apparatus. Curr Opin Cell Biol. 1994 Aug;6(4):517–521. doi: 10.1016/0955-0674(94)90070-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nokelainen P., Puranen T., Peltoketo H., Orava M., Vihko P., Vihko R. Molecular cloning of mouse 17 beta-hydroxysteroid dehydrogenase type 1 and characterization of enzyme activity. Eur J Biochem. 1996 Mar 1;236(2):482–490. doi: 10.1111/j.1432-1033.1996.00482.x. [DOI] [PubMed] [Google Scholar]
- Normand T., Husen B., Leenders F., Pelczar H., Baert J. L., Begue A., Flourens A. C., Adamski J., de Launoit Y. Molecular characterization of mouse 17 beta-hydroxysteroid dehydrogenase IV. J Steroid Biochem Mol Biol. 1995 Dec;55(5-6):541–548. doi: 10.1016/0960-0760(95)00204-9. [DOI] [PubMed] [Google Scholar]
- Peltoketo H., Isomaa V., Mäentausta O., Vihko R. Complete amino acid sequence of human placental 17 beta-hydroxysteroid dehydrogenase deduced from cDNA. FEBS Lett. 1988 Oct 24;239(1):73–77. doi: 10.1016/0014-5793(88)80548-9. [DOI] [PubMed] [Google Scholar]
- Poutanen M., Isomaa V., Peltoketo H., Vihko R. Role of 17 beta-hydroxysteroid dehydrogenase type 1 in endocrine and intracrine estradiol biosynthesis. J Steroid Biochem Mol Biol. 1995 Dec;55(5-6):525–532. doi: 10.1016/0960-0760(95)00201-4. [DOI] [PubMed] [Google Scholar]
- Poutanen M., Miettinen M., Vihko R. Differential estrogen substrate specificities for transiently expressed human placental 17 beta-hydroxysteroid dehydrogenase and an endogenous enzyme expressed in cultured COS-m6 cells. Endocrinology. 1993 Dec;133(6):2639–2644. doi: 10.1210/endo.133.6.8243287. [DOI] [PubMed] [Google Scholar]
- Qin Y. M., Poutanen M. H., Helander H. M., Kvist A. P., Siivari K. M., Schmitz W., Conzelmann E., Hellman U., Hiltunen J. K. Peroxisomal multifunctional enzyme of beta-oxidation metabolizing D-3-hydroxyacyl-CoA esters in rat liver: molecular cloning, expression and characterization. Biochem J. 1997 Jan 1;321(Pt 1):21–28. doi: 10.1042/bj3210021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sha J., Baker P., O'Shaughnessy P. J. Both reductive forms of 17 beta-hydroxysteroid dehydrogenase (types 1 and 3) are expressed during development in the mouse testis. Biochem Biophys Res Commun. 1996 May 6;222(1):90–94. doi: 10.1006/bbrc.1996.0702. [DOI] [PubMed] [Google Scholar]
- Wu J. T., Matsumoto P. S. Changing 17 beta-hydroxysteroid dehydrogenase activity in preimplantation rat and mouse embryos. Biol Reprod. 1985 Apr;32(3):561–566. doi: 10.1095/biolreprod32.3.561. [DOI] [PubMed] [Google Scholar]
- Wu L., Einstein M., Geissler W. M., Chan H. K., Elliston K. O., Andersson S. Expression cloning and characterization of human 17 beta-hydroxysteroid dehydrogenase type 2, a microsomal enzyme possessing 20 alpha-hydroxysteroid dehydrogenase activity. J Biol Chem. 1993 Jun 15;268(17):12964–12969. [PubMed] [Google Scholar]